NOVEL 1-PHENYLALKANONE 5-HT4 RECEPTOR LIGANDS

Abstract: The present invention relates to novel 5-HT4 receptor ligands which are 1-(5-halo-4-aminophenyl) (C2-6)alkan-1-one derivatives in which the 5-halo-4-aminophenyl group is substituted at its 2-position with (C1-4)alkyloxy or phenyl(C1-4)alkyloxy and optionally substituted at its 3-position with (C1-4)alkyloxy or substituted at its 2- and 3-positions together with methylenedioxy or ethylenedioxy and the highest numbered carbon of the (C2-6)alkan-1-one is substituted with di(C1-4)alkylamino, morpholin-1-yl or pyrrolidin-1-yl or optionally substituted piperidin-1-yl, piperidin-4-yl, azacyclohept-1-yl, azabicyclo[2.2.1]hept-3-yl, azabicyclo[2.2.2]oct-3-yl or azabicyclo[3.2.2]non-3-yl; and the pharmaceutically acceptable salts, individual isomers and mixtures of isomers and methods of using and making such derivatives.

Description: NOVEL 1-PHENYLALKANONE 5-HT 4 RECEPTOR LIGANDS BACKGROUND OF THE INVENTION Field of the Invention: This invention relates to novel 1-phenylalkan-l-one 5-HT 4 receptor ligands and the methods of using and preparing such ligands. Description of the Field: Serotonin, a neurotransmitter with mixed and complex pharmacological characteristics, was first discovered in 1948 and subsequently has been the subject of substantial research. Serotonin, also referred to as 5-hydroxytryptamine (5-HT) , acts both centrally and peripherally on discrete 5-HT receptors. The 5-HT receptor is presently delineated into four major subclassifications - 5-HT,, 5-HT-, 5-HT 3 and 5-HT 4 receptors - each of which may also be heterogeneous. The 5-HT 4 receptor has been identified in a wide variety of tissue and species. For example, 5-HT 4 receptors have been identified in the central nervous system (e.g., autoradiographic studies show high specific binding of high affinity 5-HT 4 receptor ligands in olfactory tubercles, stratum, substantia nigra, and superior colliculus and dorsal, medial and ventral hippocampus) . Thus, the 5-HT 4 receptor is thought to be involved in areas of the central nervous system affecting anxiety, depression, cognition, dependency, schizophrenia, appetite, etc., and drugs which interact with 5-HT 4 receptors (i.e., 5-HT 4 receptor ligands) have diverse therapeutic applications for central nervous system (CNS) disorders. 5-HT 4 Receptors are also found in the intestinal tracts of a wide variety of animal species, including man, and are found to modulate gastrointestinal motility (see Prokinetic Agents: A Key in the Future of Gastroenterology. Reynolds R.C. Gastroenterology Clinics of North America 1989, 18, 437-457) . In addition, 5-HT 4 receptors modulate smooth muscle tone of the urinary bladder (e.g., see Corεi, . ; Pietra, C; Toson, G. ; Trist, D.; Tuccitto, G.; Artibani, . Br. J. Pharmacol . 1991, 104, 719-725) and also mediate 5-HT induced positive chronotropy in right atrial tissue (e.g., see Kaumann, A.; Sanders, L. ; Brown, A.; Murray, K. ; Brown, M. ; Brown, M. Naunyn-Schmiedeberg 's. 1991, 344, 150-159) . The disclosures of these and other documents referred to throughout this application (e.g., in the Pharmacology section of the Detailed Description of the Invention) are incorporated herein by reference. SUMMARY OF THE INVENTION The first aspect of the invention is a compound of Formula I: in which R 1 is halo; R 2 is hydrogen or (C,..,)alkyloxy and R 3 is (C,_,)alkyloxy or phenyl (C M )alkyloxy (wherein the phenyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, (C M )alkyl, (C M )alkyloxy, nitro, amino, aminocarbonyl, (C M )alkylamino, di (C M )alkylamino, (C M )alkanoylamino and 3, -methylenedioxy) or R 2 and R 3 together are methylenedioxy or ethylenedioxy; and R 4 is a group of Formula (a) or (b) R 5 and R 6 are each (C M )alkyl or together form - (CO.) A - , -(CH^ j -, - (CH 2 ) 2 0(CH 2 )-- or -CHR 8 CH 2 CR 9 R 10 CHR 11 CH 2 - in which R 8 and R" are each hydrogen or together are -(CHj),- in which t is 1, 2 or 3, R 9 is hydrogen, hydroxy, (C M )alkyl, (C M )alkenyl or (C )alkyloxy and R 10 is hydrogen, (C M )alkyl or (C^)alkenyl or phenyl, thienyl, pyrrolyl or furyl (optionally substituted with one to two substituents independently selected from (C M )alkyl, (C )alkyloxy, trifluoromethyl and halo) or -(Cty-R 12 in which x is 0, 1, 2 or 3 and R 12 is hydroxy, (C )alkyloxy, -C(0)NR ,3 R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)OR 14 , -SO j NR^R' 4 , -NR 13 S0 2 R 14 , -NR^SOzNR 1 ^ 5 or -NR 13 C(O)NR 1 R 15 in which R 13 , R 14 and R 15 are independently hydrogen, (C M )alkyl, trifluoromethyl or aryl; and R 7 is hydrogen, (C,^)alkyl or (C 3 ^)alkenyl or phenyl (C )alkyl (wherein the phenyl is optionally substituted with one to three substituents independently selected from (C )alkyloxy, methylenedioxy, ethylenedioxy or halo) or -(CHjJ.R 12 in which z is 2 or 3 and R 12 is as defined above; and the pharmaceutically acceptable salts, individual isomers, and mixtures of isomers thereof. A second aspect of this invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or of an individual isomer, a mixture of isomers, or the pharmaceutically acceptable salt or salts thereof, in combination with one or more pharmaceutically acceptable excipients. A third aspect of this invention is a method for treating a condition capable of amelioration by drug interaction with 5-HT 4 receptors in an animal in need thereof, which method comprises administering to such animal a therapeutically effective amount of a compound of Formula I, or of an individual isomer, mixture of isomers, or the pharmaceutically acceptable salt or salts thereof. A fifth aspect of this invention is the processes for preparing compounds of Formula I and is set forth in "Detailed Description of the Invention" . DETAILED DESCRIPTION OF THE INVENTION Definitions: Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: "Alkyl" means a straight or branched saturated hydrocarbon radical having from one to the number of carbon atoms designated (e.g., (C M )alkyl includes the radicals methyl, ethyl, prop-1-yl, prop-2-yl, but-l-yl, but-2- yl, 2-methylpropyl and 2-methylprop-2-yl) . "Alkenyl" means a straight or branched unsaturated hydrocarbon radical having from 3 to the number of carbon atoms designated and in which the carbon atom with the free valence is saturated (e.g., (C 3 _,)alkenyl includes the radicals 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl and 2-methyl-2-propenyl) . "Alkyloxy" means the radical -OR wherein R is alkyl having from one to the number of carbon atoms designated (e.g., (C )alkyloxy includes the radicals methoxy, ethoxy, prop-1-yloxy, prop-2-yloxy, but-1-yloxy, but-2- yloxy, 2-methylprop-l-yloxy and 2-methylprop-2-yloxy) . "Alkanoyl" means the radical alkylcarbonyl having from one to the number of carbon atoms designated (e.g., (C )alkanoyl includes the radicals methanoyl, ethanoyl, propanoyl, butanoyl and 2-methylpropanoyl) . "Alkanoic acid or acid halide" means a straight saturated carboxylic acid or acid halide having 2 to 6 carbon atoms (e.g., acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, acetyl chloride, propionyl chloride, etc.) and may refer to the substituted derivatives thereof. "Alkanone or alkan-1-one" meanβ a substituted straight saturated 1-ketone having from two to the number of carbon atoms designated (e.g., (C M )alkan-l-one includes substituted ethan-1-one, propan-1-one, butan-1-one, pentan-l-one, and hexan-1-one) . "Aryl" means an organic radical derived from an aromatic hydrocarbon and includes monocyclic or condensed carbocyclic aromatic groups having from 6 to 20 carbon atoms (e.g., phenyl, naphthyl and the like) . "Halo" means fluoro, chloro, bromo or iodo. "Leaving group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions, and includes halo and alkane- or arenesulfonyloxy, such as mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosyloxy, and alkanesulfonylamino, alkanecarbonylamino, airtinosufonylamino, aminocarbonylamino, and the like. "Protective group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e., a group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site. "Deprotection" or "deprotecting" is the process by which a protective group is removed after the selective reaction is completed. Certain processes of this invention rely upon protective groups to block reactive nitrogen atoms present in the reactants. Acceptable amino protecting groups include acetyl and tert-butoxycarbonyl, which may be readily removed by acid hydrolysis. "Animal" includes humans, non-human mammals, e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, and deer, and non- ammals, e.g., birds and the like. "Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted with one to two substituents" means that the substituents may or may not be present in order for the compound described to fall within the invention, and the invention includes those compounds wherein one to two substituents are present and those compounds in which no substituents are present. "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that iβ generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable salts" means salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, εulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethaneεulfonic acid, 1,2, -ethanediεulfonic acid, 2-hydroxyethanesulfonic acid, benzeneεulfonic acid p-chlorobenzeneεulfonic acid, 2-naphthaleneεulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4' -methylenebis (3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl εulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, εalicylic acid, stearic acid, muconic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potaεεium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, -J-methylglucamine and the like. "Therapeutically effective amount" means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease. "Treating" or "treatment" of a disease includes: (1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting its development, or (3) relieving the disease, i.e., causing regression of the disease. The compounds of Formula I are named in accordance with acceptable nomenclature rules generally consistent with "Chemical Abstracts". For example, the compound of Formula I in which R 1 is chloro, R 3 is methoxy and R 4 is a group of Formula (a) , in which n is 4, p is 0, and R 5 and R 6 are each methyl is named 1- (4-amino-5-chloro-2-methoxyphenyl) -5-dimethylaminopentan-l-one. Presently Preferred Embodiments: The compounds of this invention are (C-_s)alkan-1-ones derivatives having a substituted phenyl moiety at the 1-position and a nitrogen containing moiety at the highest numbered position. The nitrogen containing moiety may be (N,_v"-diεubεtituted)amino, (l-substituted)piperidin-4-yl, morpholin-1-yl or pyrrolidin-l-yl or optionally substituted piperidin-1-yl, azacyclohept-1-yl, azabicyclo[2.2.1]hept-3-yl, azabicylo[2.2.2]oct-3-yl or azabicylo[3.2.2]non-3-yl. Compoundε of Formula I in which R 2 is hydrogen, R 3 is (C M )alkyloxy and R 4 is a group of Formula (a) are designated compounds of Formula I (a) l(o) in which n is 3, 4 or 5; p is 0 or 1; R 1 is halo; and R 5 and R 6 are each (C M )alkyl or together form - HA) 4 - , - (CH ) 6 - , -(CH j ^O CH^- or -CHR 8 CH 2 CR 9 R 10 CHR U CH 2 - in which R 8 and R u are each hydrogen or together are -(CH_),- in which t is 1, 2 or 3, R 9 is hydrogen, hydroxy, (C,.g)alkyl, (C M )alkenyl or (C )alkyloxy, and R 10 is hydrogen, (C,^) lkyl or (C j ^)alkenyl or phenyl, thienyl, pyrrolyl or furyl (optionally substituted with one to two substituents independently selected from (C,^)alkyl, (C )alkyloxy, trifluoromethyl and halo) or -(CH^.R 12 in which x is 0, 1, 2 or 3 and R 12 is hydroxy, (C M )alkyloxy, -C(0)NR 13 R 14 , -NR 13 C(O)R 14 , -NR I3 C(O)OR 14 , -S0jNR 13 R 14 , -NR 13 S0 2 R 14 , -N I3 S0 2 R 14 R 15 or -NR I3 C(0)NR l4 R 15 in which R 13 , R 14 and R 15 are independently hydrogen, (C )alkyl or trifluoromethyl; and the pharmaceutically acceptable salts, individual isomers, and mixtures of isomers thereof. Compounds of Formula I which R 2 is hydrogen or (C M )alkyloxy and R 3 is (C )alkyloxy or R 2 and R 3 together are methylenedioxy or ethylenedioxy and R 4 is a group of Formula (b) are designated as compounds of Formula I (b) : in which p is 0 or 1; q is 1 or 2; R 1 iε halo; and R 7 iε hydrogen, (C^)alkyl, ( ^)alkenyl or phenyl (C M )alkyl (wherein the phenyl is optionally substituted with one to three substituents independently selected from (C M )alkyloxy, methylenedioxy, ethylenedioxy or halo) or -(oy.R 12 in which z iε 2 or 3 and R 12 is hydroxy, (C )alkyloxy, -C(0)NR l3 R 14 , -NR 13 C(0)R 14 , -NR ,3 C(0)OR 14 , -NR 13 S0 2 R 14 , -NR 13 S0 2 NR I4 R 15 or -NR 13 C(0)NR I4 R 15 in which R 13 , R' 4 and R 15 are independently hydrogen, (C )alkyl, trifluoromethyl or aryl; and the pharmaceutically acceptable salts, individual isomers, and mixtures of isomers thereof. Compounds of Formula I in which R 2 is hydrogen and R 3 is (C M )alkylphenyloxy (wherein the phenyl is optionally substituted with one to three εubεtituents independently selected from halo, hydroxy, (C )alkyl, (C )alkyloxy, nitro, amino, aminocarbonyl, (C M )alkylamino, di (C M )alkylamino, (C )alkanoylamino and 3,4-methylenedioxy) are deεignated aε compounds of Formula I (c) : 1(e) in which R 1 is halo; and R 4 iε a group of Formula (a) or (b) : in which n iε 3, 4 or 5; p is 0 or 1; q is 1 or 2; R 5 and R 6 are each (C,_,)alkyl or together form -(CH 2 ) 4 -, -(CH 2 ) 6 -, - (CH 2 ) 2 0(CH 2 ) 2 - or -CHR 8 CH 2 CR 9 R 10 CHR"CH 2 - in which R 8 and R" are each hydrogen or together are -(CH 2 ),- in which t iε 1, 2 or 3, R 9 is hydrogen, hydroxy, (C w )alkyl, (Cj*)alkenyl or (C )alkyloxy and R 10 iε hydrogen, (C w )alkyl or alkenyl or phenyl, thienyl, pyrrolyl or furyl (optionally substituted with one to two subεtituentε independently selected from (C M )alkyl, (C M )alkyloxy, trifluoromethyl and halo) or - (CH 2 )-R 12 in which x is 0, 1, 2 or 3 and R 12 iε hydroxy, (C,_,)alkyloxy, -C(0)NR 13 R 14 , -NR 13 C(0)R M , -NR 13 C(O)OR' 4 , -S0 2 NR ,3 R'\ -NR 13 S0 2 R 14 , -NR 13 S0 2 NR 14 R 15 or -NR 13 C (O) NR 14 R 15 in which R 13 , R 14 and R 15 are independently hydrogen, (C )alkyl or trifluoromethyl; and R 7 is hydrogen, (C^)alkyl or (C 3 ^)alkenyl or phenyl (C )alkyl (wherein the phenyl is optionally substituted with one to three substituents independently selected from (C )alkyloxy, methylenedioxy, ethylenedioxy or halo) or - (CH^-R 12 in which z iε 2 or 3 and R 12 iε as defined above; and the pharmaceutically acceptable εaltε, individual iεomers, and mixtures of iεomerε thereof. While the breadth of compounds which are intended by the invention is as set forth in the Summary of the Invention, certain compounds are preferred. For example, preferred compounds are compounds of Formula 1(a) in which n is 4 and R 5 and R 6 together form -CHR 8 CH 2 CR 9 R I0 CHR"CH 2 - ; and compounds of Formula 1(b) in which q iε 2; and compounds of Formula 1(c) in which R 4 is a group of Formula (a) wherein n is 4 and R 5 and R 6 together form -CHR 8 CH-CR 9 R K -HR"CH 2 - or in which R 4 is a group of Formula 1(b) wherein q is 2. Particularly preferred are compounds of Formula 1(a) in which n is 4, R 1 is chloro, R 3 is methoxy, and R 5 and R 6 together form -CH 2 CH 2 CHR I0 CH 2 CH 2 - wherein R 10 is hydrogen, (C,^)alkyl or - (0_ 2 )_R 12 ; and compounds of Formula 1(b) in which q is 2, R 1 is chloro, R 3 is methoxy, and R 7 is hydrogen, (C,_g)alkyl or - (CH_).R 12 ; and compounds of Formula 1(c) in which R 1 is chloro, R 3 is 3,5-dimethoxy-benzyloxy, and R 4 is a group of Formula (a) wherein n is 4 and R 5 and R 6 together form wherein R 10 is hydrogen, (C,^)alkyl or -(oy- 12 or R 4 is a group of Formula (b) wherein q is 2 and R 7 is hydrogen, (C,^)alkyl or -(0_ 2 )_R 12 . Most preferred are the following compounds of Formula I (a) : 1- (4-amino-5-chloro-2-methoxy-phenyl) -5- (piperidin-l-yl)pentan-l-one, 1- (4-amino-5-chloro-2-methoxyphenyl) - 5- (4-methylpiperidin-l-yl)pentan-l-one, 1- (4-amino-5-chloro-2- methoxyphenyl) - 5- (4-aminocarbonylpiperidin-l-yl) -pentan-1-one, 1- (4-amino-5-chloro-2-methoxyphenyl) - 5-{4- [ (methylsulfonyl)amino]piperidin-l-yl}pentan-l-one; and the following compounds of Formula I (b) : 1- (4-amino-5-chloro-2-methoxyphenyl) -3- (1- methylpiperidin-4-yl)propa -1-one, 1- (4-amino-5-chloro-2-methox phenyl) -3- (l-ethylpiperidin-4-yl)propan-l-one, 1- (4-amino-5-chloro-2-methoxyphenyl) - 3- [1- (prop-l-yl)piperidin-4-yl]propan-l-one, 1- (4-amino-5-chloro-2-methoxyphenyl) - 3- [1- (but-l-yl)piperidin-4-yl]propan-l-one, 1- (4-amino-5-chloro-2-methoxyphenyl) - 3- [1- (pent-l-yl)piperidin-4-yl]propan-l-one, 1- (4-amino-5-chloro-2-methoxyphenyl) - 3-{l- [2- (methylεulfonyl)aminoethyl]piperidin-4-yl}propan-l-one, 1- (4-amino-5-chloro-2-methoxyphenyl) - 3-{l- [2- (dimethylaminosulfonyl)aminoethyl]piperidin-4-yl}propan-l-one, 1- (4-amino-5-chloro-2-methoxyphenyl) - 3-{l- [3- (methylsulfonyl)aminoprop-l-yl]piperidin-4-yl}propan-l-one; 1- (4-amino-5-chloro-2,3-dimethoxyphenyl) - 3- [1- (3-butyl-l-yl)piperidin-4-yl]propan-l-one; 1 - (4 -amino-5 -chloro-2 , 3 -ethylenedioxyphenyl) - 3 - [1 - ( 3 -butyl - 1 -yD piperidin- 4 -yl] propan- 1- one ; 1- (4 -amino-5 - chloro-2 -methoxyphenyl) - 3 - {l- [3 - (4 -methoxyphenyl) prop-l -yl] piperidin-4 -yl}propan-l-one ; 1 - (4 -amino-5 -chloro-2 -methoxyphenyl) - 3-{l- [3- (2,3,4-trimethoxyphenyl)prop-l-yl]piperidin-4-yl}propan-l-one; 1- (4-amino-5-chloro-2-methoxyphenyl) - 3-{l- [3- (3,4-methylenedioxyphenyl)prop-l-yl]piperidin-4-yl}propan-l-one; 1- (4-amino-5-chloro-2-methoxyphenyl) - 3-{l- [3- (3,4-ethylenedioxyphenyl)prop-1-yl]piperidin-4-yl}propan-1-one; 1- (4-amino-5-chloro-2-methoxyphenyl) - 3-{l- [3- (3,4-dimethox phenyl)prop-1-yl]piperidin-4-yl}propan-1-one,- 1- (4-amino-5-chloro-2-methoxyphenyl) - 3-{l- [3- (3,5-dimethoxyphenyl)prop-l-yl]piperidin-4-yl}propan-l-one; 1- (4-amino-5-chloro-2,3-ethylenedioxyphenyl) - 3-{l- [3- (4-methoxyphenyl)prop-l-yl]piperidin-4-yl}propan-l-one; and the following compounds of Formula I (c) : 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5- (piperidin-l-yl)pentan-l-one, 1- [ -amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5- (4-methylpiperidin-1-yl)pentan-1-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5- [4- (prop-l-yl)piperidin-l-yl]pentan-l-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5-{4- [2- (methylsulfonyl)aminoethyl]piperidin-l-yl}pentan-l-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5- [4- (methylsulfonyl)aminomethylpiperidin-1-yl]pentan-1-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5- [4- (aminocarbonyl)aminomethylpiperidin-l-yl]pentan-1-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5- (4-aminocarbonylpiperidin-1-yl)pentan-1-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5- (4-hydroxypiperidin-1-yl)pentan-1-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5- (4-methoxypiperidin-1-yl)pentan-1-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5- [4- (aminocarbonyl)aminopiperidin-l-yl]pentan-l-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5- [4- (methylsulfonyl)aminopiperidin-l-yl]pentan-l-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 3- [1- (but-l-yl)piperidin-4-yl]propan-l-one, 1- [ -amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 3- [1- (pent-l-yl)piperidin-4-yl]propan-l-one, 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 3-{l- [2- (methylsulfonyl)aminoethyl]piperidin-4-yl}propan-l-one; or the pharmaceutically acceptable salts, preferably the hydrochloride salts, thereof. Pharmacology and Utility: The compounds of the invention interact with 5-HT 4 receptors (i.e., the compounds have affinity for 5-HT 4 receptors and exhibit agonist or antagonist properties) . The 5-HT 4 receptor interactant properties of test compounds are identified by an assay which utilizes rat, isolated thoracic esophageal muscle (i.e., test compounds which intrinsically produce relaxation are characterized as 5-HT receptor agonists, while test compounds which inhibit agonist-induced, 5-HT 4 receptor mediated relaxation responseε are characterized aε 5-HT 4 receptor antagonists) . The rat, isolated thoracic esophagus muscle is well established as a model for identifying and characterizing compounds that interact with 5-HT 4 receptors (e.g., see Baxter, G.S.; Craig, D.A.; Clarke, D.E. Naiin n-Sci-miedeJbergr's Arch. Pharmacol. 1991, 343, 439-446) and is described in Example 17. As 5-HT 4 receptor ligands, the compounds of this invention are useful for treating conditions which can be ameliorated by interaction with 5-HT 4 receptorε. Such conditionε include CNS diεorders, gastrointestinal diεorderε, cardiovascular disorders, and urinary tract disorders. Particular CNS disorderε include a variety of neurologic and pεychiatric diεorders such as cognitive disorders, psychoseε, and obsessive/compulsive and anxiety/depression behavior. Cognitive diεorderε include attentional or memory deficit, dementia states (including senile dementia of the Alzheimer's type and aging), cerebral vascular deficiency and Parkinson's disease. Psychoses which may be treatable with the compounds of this invention include paranoia, schizophrenia and autiεm. Obsessive/compulsive behavior includeε eating diεorderε (e.g., bulimia, a condition in which an abnormal and constant craving for food is present) . Anxiety/depressive states include anticipatory anxiety (e.g., prior to surgery, dental work, etc.), depression, mania, seaεonal affective disorder (SAD) , and the convulsions and anxiety caused by withdrawal from addictive substances such aε opiates, benzodiazapines, nicotine, alcohol, cocaine and other drugs of abuse. Particular intestinal diεorderε include diseases which relate directly or indirectly to gastromotility of the εtomach, eεophaguε and of both the large and εmall inteεtineε. Specific diseases include, but are not limited to, dyspepsia (e.g., non-ulcer dyspepsia), gastric stasis, peptic ulcer, reflux esophagitiε, flatulence, bile reflux gastritis, pseudo-obstruction syndrome, irritable colon syndrome (which may result in chronic constipation and diarrhea) , diverticular disease, biliary dyεmotility (which may result in εphincter of Oddi dysfunction and "sludge" or microscopic crystals in the gall bladder) , gastropareεiε (e.g., diabetic, postsurgical or idiopathic) , irritable bowel syndrome and retarded gastric emptying. Other uses include short-term prokinesis to facilitate diagnostic radiology and intestinal intubation and for treating diarrhea, particularly diarrhea induced by cholera and carcinoid syndrome. Particular cardiovascular disorders include diseases which relate directly or indirectly to cardiac arrhythmias. Particular urinary tract disorderε include diεeases which relate directly or indirectly to dysfunction of urinary smooth muscle or innervation causing inadequate urinary storage or control or urinary stasis and which may result in infection, calculi or renal damage. In general, the particular condition that a compound of this invention may be useful in treating will depend upon whether the compound exhibits agonist qualities or antagonists qualities. For example, certain compoiuαds of this invention which are 5-HT 4 receptor agonists are useful as prokinetic agents in treating diseases in which gastric motility is impaired or for enhancing ureteral smooth muscle tone in treating urinary tract diseases in which the bladder is hypotonic or as cognition enhancing agents for treating conditions which directly or indirectly relate to cognition deficit. In contrast, the compounds which are 5-HT 4 receptor antagonists can block 5-HT 4 receptor mediated peristalsis and are useful in treating diseases involving hypermotility states or can block 5-HT 4 receptor mediated contractions of ureteral smooth muscle and are useful in the treatment of diseases involving spasticity of the bladder or can block 5-HT 4 receptor mediated positive chronotropy and are useful as antiarrhythmic agents. While the condition for which any given compound of this invention may be useful largely depends upon the antagonist or agonist qualities of the given compound, certain individual variations may occur. Thus, the 5- HT 4 receptor ligands of this invention may be further tested by in vivo or in vitro methodologies designed to determine therapeutic activity. For example, the prokinetic activity of compounds of this invention can be determined by measuring the increase in rate of gastric emptying in ratε after oral administration of test compound. The rat, prokinetic assay is a well established model for identifying compounds that posεesε prokinetic activity (e.g., εee Droppleman, D.; Gregory, R. ; Alphin, R.S. J. Pharmacol . Methods 1980, 4 (3) , 227-30) and is described in Example 18. The cognitive enhancing properties of compounds of this invention can be determined by using the Morris Water Maze Assay, which measures changes in the cognitive performance of rats. The Morris Water Maze Assay is a well established model for demonstrating cognition enhancing activity (e.g., see Morris, R.G.M.; Garrud, P.; Rawlins, J.N.P.; O'Keefe, J. ivature. 1982, 257, 681-683) and is described in Example 21. Anxiolytic activity is determined by the art-recognized Crawley and Goodwin two-compartment exploratory model (e.g., see Kilfoil, T. ; Michel, A.; Montgomery, D.; Whiting, R.L. Neuropharmacology 1989, 28 (9) , 901-905) . In brief, the method measureε the extent a compound affectε the natural anxiety of mice in a novel, brightly lighted area. The anxiolytic behavior assay is described in Example 19. Anxiolytic activity during withdrawal from drugs of abuse iε determined by the mouse, withdrawal anxiety test, an accepted assay (e.g., see Carboni, E.,- Acquas, E.; Leone, P.; Perezzani, L. ; Di Chiara, G. Eur. J. Pharmacol 1988, 151, 159-160) . This procedure utilizes the exploratory model described above to measure the extent a compound ameliorates the symptoms of withdrawal that occur after chronically treating with an addictive substance and then abruptly ceasing the treatments. The withdrawal anxiety assay is described in Example 20. In summary, the compounds of this invention are useful for treating conditions which can be ameliorated by interaction with 5-HT 4 receptors. Such conditions include CNS disorders, gastrointeεtinal disorders, cardiovascular disorders, and urinary tract disorders. In particular, the compounds are useful for treating conditions relating to cognitive disorders, gastric hypomotility, irritable bowel syndrome, arrhythmia, hypotonicity of the bladder, or spasticity of the bladder. Administration and Pharmaceutical Composition: In general, compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another compound of Formula I or with another therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. A therapeutically effective amount may range from approximately 0.01 milligram per Kg (mg/Kg) body weight per day to 10 mg/Kg body weight per day. Preferably the amount will be approximately 0.1 to 1 mg/Kg/day. Therefore, a therapeutically effective amount for a 70 Kg human may range from 0.7 to 700 mg/day, preferably 7 to 70 mg/day. One of ordinary skill in the art of treating such diεeaεeε will be able, without undue experimentation and in reliance upon perεonal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of a compound of Formula I for a given disease. In general, compounds of the invention will be administered aε pharmaceutical compoεitionε by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by εuppoεitory) or parenteral (e.g., intramuεcular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsuleε, semisolidε, powders, εuεtained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adverεely affect the therapeutic benefit of the compound of Formula I. Such excipient may be any solid, liquid, semiεolid or, in the caεe of an aeroεol compoεition, gaεeous excipient that is generally available to one of εkill in the art. Solid pharmaceutical excipientε include εtarch, celluloεe, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, εodium chloride, dried εkim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols. Compressed gases may be used to disperse the compound of the invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, nitrous oxide, etc. Other suitable pharmaceutical carriers and their formulations are described in A.R. Alfonso Remington ' s Pharmaceutical Sciences 1985, 17th ed. Easton, Pa.: Mack Publishing Company. The amount of a compound of the invention in the compoεition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, the final composition will comprise from 25%w to 75%w of the compound of Formula I, preferably 30%w to 50%w, with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of Formula I are described in Example 16. Processeε for Preparing Compounds of the Invention: A method for making compounds of Formula I iε depicted by the following Reaction Scheme I: REACTION SCHEME I J. ACIiir ICATION 4. ICCAtiOITLATION in which each R 1 , R 2 , R 3 and R 4 are as defined in the Summary of the Invention, with the reactions applying particularly well to the presently preferred embodiments. The compounds of Formula I can be prepared by a process which comprises reacting a compound of Formula II, or a protected derivative thereof, with a compound of Formula III, acidifying, decarboxylating, and when necessary removing any protective groups. The reaction between the compounds of Formulae II and III is carried out in the presence of a strong base (e.g., lithium diisopropylamide) and in a suitable solvent (e.g., tetrahydrofuran (THF) and hexamethylphosphoric triamide (HMPA) , preferably a 50/50 mixture of THF and HMPA) at -40 to 0°C. The reaction mixture is then acidified and extracted into an appropriate solvent (e.g., methylene chloride) . The decarboxylation can then be carried by standard methods to form a compound of Formula I. The preparation of a compound of Formula I by the process depicted in Reaction Scheme I iε described in Example 3. Compounds of Formula II in which R 4 is a group of Formula (a) can be prepared by reacting a halofC^)alkionate with a compound of the formula NHR 5 R 6 to give an aminated (C^)alkionate and then hydrolyzing and converting to the acid addition salt. The reaction with the compound of the formula NHR 5 R 6 is carried out in a suitable solvent (e.g., l-methyl-2- pyrrolidinone, DMF, etc.) at 25 to 50°C, preferably at approximately 35°C, and requires 12 to 48 hourε. The hydrolyεiε can be effected with acid (e.g., hydrochloric acid, εulfuric acid, etc.) at 90 to 110°C, preferably at approximately 100°C, and requires 2 to 4 hours. The acid addition salt can be recovered by crystallization from the solvent (e.g., by diluting with acetone) . Compounds of Formula II in which R 4 iε a group of Formula (b) may be prepared from an appropriately 1-substituted 4-hydroxypiperidine or 4-hydroxymethylpiperidine. The 4-piperidinealcohol iε converted to the correεponding εulfonate (i.e., to 4- (p-tolueneεulfonyloxy)piperidine or 4- [ (p-tolueneεulfonyloxy)methyl]piperidine) by reacting with p-tolueneεulfonyl chloride. The εulfonate iε then reacted with diethyl malonate in the presence of base to produce a 4- [di (ethoxycarbonyl)alkyl]piperidine. The 4- [di (ethoxycarbonyl)alkyl]piperidine is then converted to a dicarboxylic acid which upon decarboxylation gives a compound of Formula II. Protected derivatives of compounds of Formula II are prepared from the protected derivative of the piperidinealcoholε (e.g., 1-tert-butoxycarbonyl-4-piperidinemethanol) . The preparation of a protected derivative of Formula II in which R 4 is Formula (b) is described in Example 1. The compounds of Formula III can be prepared by reacting an appropriate 4-amino-5-halobenzoic acid with N,0-dimethylhydroxylamine hydrochloride. The reaction is carried out in the presence of carbonyldiimidazole in a suitable solvent (e.g., N, , -dimethylformamide (DMF) ) . The preparation of a compound of Formula III is described in Example 2. Alternatively, compounds of Formula I in which R 4 is a group of Formula (b) and R 7 is not hydrogen can be prepared by alkylating a corresponding compound of Formula I in which R 7 is hydrogen with a compound of the formula L-R 20 in which L is a leaving group and R 20 is (C w )alkyl, (C^ 8 )alkenyl, phenyl (C,^)alkyl (wherein the phenyl is substituted as defined in the Summary of the Invention) or -(CH^.R 12 (wherein z and R 12 are as defined in the Summary of the Invention) . The alkylation is carried out under standard amide alkylating conditions (Luh, T.; Fung S.H. Synth. Commun. 1979, 9, 757), in an inert solvent (e.g., acetonitrile, DMF, THF, etc.), and at a reaction temperature of 20°C to 100°C and requires 1 to 48 hours. The alkylation can also be carried via a phase-transfer catalyst (PTC) system, i.e., with catalyst in a liquid-liquid two phase solvent system (Gajda, T.; Zwierzak, A. Synthesis, Communications 1981, 1005), or preferably a solid-liquid system (Yamawaki, J.; Ando, T.; Hanafusa, T. Che . Lett. 1981, 1143; Koziara, A.; Zawaszki, S; Zwierzak, A. Synthesis 1979, 527, 549) . A liquid-liquid two-phase syβtem iε comprised of an aqueous phase consisting of a concentrated alkali hydroxide solution (e.g., 50% aqueous sodium hydroxide) , an organic phase comprised of an inert water-immiscible organic solvent, and an appropriate catalyst. A solid-liquid system consists of a powdered alkali hydroxide/alkali carbonate suspended in an organic solvent and catalyst. The reaction is effected by slowing adding the alkylating agent to a PTC syεtem containing the compound of Formula I until the alkylating agent iε 10 to 50% in exceεε. The reaction mixture iε kept at reflux until the reaction iε complete. The mixture iε then cooled to room temperature and the product iε isolated by conventional methods. Suitable organic solvents include benzene, toluene, and the like. Appropriate catalyεtε include alumina coated with potaεsium fluoride and quaternary ammonium sulfateε such aε tetra-n-butylammonium hydrogen sulfate and tricaprylylmethylammonium chloride. The alkylation of a compound of Formula 1(b) in which R 7 is hydrogen is described in Example 10. Compounds of Formula I in which R 4 is a group of Formula (b) and R 7 is - (CH 2 ) 2 NHC(0)R 14 , - (CH 2 ) 2 NHSθ 2 R 14 , - (CH 2 ) 2 NHS0 2 NR l4 R 15 or - (CH 2 ) 2 NHC(O)NR I R 15 (wherein R' 4 and R 15 are as defined in the Summary of the Invention) can be prepared by alkylating a compound of Formula I in which R 7 iε hydrogen with a compound of the formula X-R 21 in which X iε azacycloprop-1-yl and R 21 iε - C(0)R 9 , -S0 2 R 14 , -SOjNR"-. 15 or -C(0)NR l4 R 15 . The alkylation iε carried out in a εuitable εolvent (e.g., THF) at 0 to 20°C. The preparation of a compound of Formula 1(b) in which R 7 iε 2- [ (methylεulfonyl)amino] ethyl iε deεcribed in Example 11. A method for making compounds of Formula I in which R 2 is hydrogen and R 4 is a group of Formula (a) is depicted by the following Reaction Scheme II: REACTION SCHEME II 3. I-*', ,C0, 4. MHR*I»• 5. DEPROTECTION in which P is a protective group, R 18 is halo or hydroxy, R 19 is halo and L is a leaving group and each n, R 1 , R 3 , R 5 and R 6 are as defined in the Summary of the Invention. The compounds of Formula I in which R 2 is hydrogen and R 4 is a group of Formula (a) (Formula IV) can be prepared by a procesε which comprises reacting a compound of Formula V with a compound of Formula VI; alkylating with a compound of the formula L-R 3 ; reacting with a compound the formula HNR 5 R 6 , or the i\t-oxide thereof; and removing the protective group. The reaction between the compound of Formula V and the compound of Formula VI is carried out in the presence of a Lewiε acid (e.g., aluminum chloride (A1C1 3 ) , boron trifluoride, hydrogen fluoride, phoεphosporic acid, etc., preferably A1C1 3 ) and in a suitable solvent (e.g., ethylene dichloride (EDC) , methylene chloride, carbon disulfide, etc., preferably EDO to form a 2-hydroxyphenylalkanone. Alkylation of the 2-hydroxyphenylalkanone with the compound of the formula L-R 3 is carried out in the presence of potasεium carbonate in a εuitable εolvent (e.g., methyl ethyl ketone (MEK) , DMF, ethanol, THF, etc., preferably MEK) at 40 to 200°C. The reaction with the compound of the formula HNR 5 R 6 is carried out in a εuitable solvent (e.g., DMF, ethanol, THF, toluene, etc., preferably DMF) at 40 to 200°C. Deprotection can be carried out by any meanε that selectively removeε the protective group. The preparation of a compound of Formula I (a) by the above proceεs is described in Example 4. The compounds of Formula VI are either available commercially (e.g., 5-chlorovaleric acid and 5-chlorovaleryl chloride) or can otherwise be readily prepared by halogenation of the corresponding alkanoic acid. The N-acetyl-halo-5-methoxyanilines of Formula V are either commercially available or can otherwise be obtained from tv"-acetyl -3 -methoxyaniline . For example, a compound of Formula V in which R 1 iε bromide can be prepared by reacting .N-acetyl-3-met__oxyaniline with bromine in a εuitable solvent (e.g., dichloroethane) . The compounds of the formula HNR 5 R 6 (e.g., --mines such as dimethylamine, diethylamine, diprop-1-ylamine, etc., and azacycloalkanes such as pyrrolidine, piperidine, pyrrolidine, morpholine, 4-phenylpiperidine, 4-methylpiperidine, etc.) are known and available commercially or otherwise can be synthesized by methodε known to those of ordinary skill in the art. In variations upon Reaction Scheme II, compounds of Formula I may be prepared by reacting, in the presence of a Lewis acid, a compound of Formula V with a compound of Formula VI; reacting with a compound of the formula HNR 5 R 6 , or the it-oxide thereof; alkylating with a compound of the formula L-R 3 ; and removing the protective group; or by reacting a compound of Formula VI with a compound of the formula HNR 5 R 6 , or the N-oxide thereof; reacting, in the presence of a Lewis acid, with a compound of Formula V; alkylating with a compound of the formula L-R 3 ; and removing the protective group. A method for making compounds of Formula I in which R 4 is a group of Formula (b) wherein q iε 2 and R 7 iε hydrogen is depicted by the following Reaction Scheme III: REACTION SCHEME III VI I I DEHYDRAT ION VI I HYDROGEN*T ION in which R 1 , R 2 , R 3 and R 7 are aε defined in the Summary of the Invention. Compounds of Formula I in which R 4 is a group of Formula (b) wherein p is 0, q is 2 and R 7 is hydrogen can be prepared by a process which comprises reacting a compound of Formula VIII with a compound of Formula IX to give a 3-pyridin-4-yl-3-hydroxy-propan-l-one derivative, dehydrating the 3-hydroxypropan-l-one to give a 3-pyridin-4-ylpropen-l-one derivative, and then hydrogenating to give the corresponding 3-piperidin-4-yl-propan-l-one. The reaction between the compounds of Formulae VIII and IX is carried out in the presence of a strong base (e.g., lithium diisopropylamide) in a suitable solvent (e.g., THF) at -50 to 50 β C. Dehydration of the 3-hydroxypropan-l-one is carried out by standard methods (e.g., acid-catalyzed dehydration) . If the reaction between the compound of Formulae VTII and IX is carried out in the presence of potassium hydroxide, the dehydration occurs spontaneously and the reaction proceeds to the 3-pyridin-4-yl-2-propen-l-one in a single step. Hydrogenation of the 3-pyridin-4-yl-2-propen-l-one is carried out by with an appropriate catalyst (e.g., 5% rhodium-alumina, 10% palladium on carbon, platinum dioxide, palladium dihydroxide, etc.) in a εuitable εolvent (e.g., acetic acid, ethanol, DMF, THF, etc.) at 5 to 60 pεi and requires 1 to 48 hours. The preparation of a compound of Formula 1(b) by the process characterized above is described in Example 7. Alternatively, hydrogenation of the 3-pyridin-4-yl-2-propen-l-one iε carried out by (i) hydrogenating the 2-propen-l-one until conversion to the corresponding 3-pyridin-4-ylpropan-l-one iε complete, (ii) optionally alkylating the propan-1-one with a compound of the formula L-R 20 or X-R 21 (wherein R 20 and R 21 are aε defined above) , and then (iii) continuing hydrogenation to give the corresponding 3-piperidin-4-ylpropan-l-one. Hydrogenation of the propenone to the 3-pyridin-4-ylpropan-l-one iε carried out with an appropriate catalyεt (5% palladium on carbon, 20% palladium hydroxide, etc.) in a suitable solvent (e.g., THF, acetic acid, DMF, ethanol, etc.) at 5 to 60 psi and requireε 1 to 48 hours. The preparation of a compound of Formula 1(b) in which R 7 is 3- (4-methoxyphenyl)prop-l-yl is described in Example 13. The optional reaction with the compound of the formula L-R 20 or X-R 21 is carried out as described above for the alkylation of compounds of Formula I in which R 4 is a group of Formula (b) and R 7 is hydrogen. Hydrogenation of the 3-pyridin-4-yl-propan-l-one is carried out by with an appropriate catalyst (e.g., 5% rhodium-alumina, 10% palladium on carbon, platinum dioxide, palladium dihydroxide, etc.) in a εuitable εolvent (e.g., acetic acid, ethanol, DMF, THF, etc.) at 5 to 60 psi and requires 1 to 48 hourε. The compoundε of Formula VTII can be prepared by methylation of the corresponding W-methoxy-.W-methylbenzamide. The methylation is carried out by reacting the _\t-methoxy-t'-methylbenzamide with methylating agent (e.g., methyllithium, methyl magnesium bromide, etc.) in a εuitable solvent (e.g., THF, ether, etc.) at -20 to 20°C and requires 1 to 24 hourε. The preparation of a compound of Formula VIII in which R 1 iε chloro and R 3 iε methoxy is described in Example 5. Alternatively, compounds of Formula VIII in which R 2 and R 3 together are ethylenedioxy can be prepared by halogenating a protected derivative of 4' -amino-2' ,3' -ethylenedioxyacetophenone and then deprotecting. The halogenation can be carried out by reacting the acetophenone with a halogenating agent (e.g., W-chlorosuccinimide, chlorine, etc.) in a suitable solvent (e.g., DMF, acetonitrile, etc.) at -20 to 80°C and requireε 1 to 24 hourε. Deprotection can be carried out with baεe (e.g., sodium hydroxide and the like) in a suitable εolvent (e.g., methanol and the like) . The 4' -amino-2' ,3' -ethylenedioxyacetophenone can be prepared by reacting 5' ,6' -dichloro-2' ,3' -ethylenedioxyacetophenone with fuming nitric acid to give 5' ,6' -dichloro-2' ,3' -ethylenedioxy-4' -nitroacetophenone and then reducing. The reaction with the nitric acid iε carried out at 0 to 25°C and requireε 0.5 to 2 hourε. The reduction is carried out in the presence of catalyεt (e.g., 10% palladium on carbon) in a εuitable solvent (e.g., ethanol, acetic acid, ethyl acetate, etc.) at room temperature and requireε 1 to 24 hourε. Protection of the 4' -amino- 2' ,3' -ethylenedioxyacetophenone can be effected by reacting with a suitable protecting agent. For example, 2' ,3' -ethylenedioxy- 4' - (methylcarbonylamino)acetophenone is prepared by reacting the unprotected acetophenone with acetic anhydride in pyridine. The reaction with the acetic anhydride is carried out at 0 to 30°C and requireε 1 to 8 hourε. The 5' , 6' -dichloro- ' ,3 ' -ethylenedioxy-4 ' -nitroacetophenone can be prepared by chlorinating 1,4-benzodioxane to give 6,7-dichloro-l,4- benzodioxane and then acetylating. The chlorination can be carried out by treating the benzodioxane with chlorine gas in acetic acid at 0 to 20°C and requires 1 to 8 hours. The acetylation can be effected by reacting the 6,7-dichloro-1,4-benzodioxane with acetyl chloride in the presence of a Lewis acid in a suitable solvent (e.g., 1,2-dichloroethane, carbon disulfide, nitrobenzene, etc.) at 20 to 40°C and requires 24 to 48 hourε. A method for making compounds of Formula I in which R 4 is a group of Formula (a) iε depicted by the following Reaction Scheme IV: REACTION SCHEME IV in which each P is a protective group and R 1 , R 2 , R 3 , R 5 and R 6 are aε defined in the Summary of the Invention. Compounds of Formula I in which R 4 is a group of Formula (a) can be prepared by a process which comprises treating a compound of Formula XI with magnesium to give a Grignard reagent, reacting the Grignard reagent with a compound of Formula XII to give the corresponding protected (C,_ 6 )alkanone, deprotecting and then reacting the unprotected alkanone with a compound of the formula NHR 5 R*. The treatment with the magnesium is carried out by adding the compound of Formula XI under nitrogen to a suspension of magnesium in a suitable solvent (e.g., THF, diethyl ether, etc.) at a rate such that the liberation of heat is controlled and then allowing the reaction to proceed at 20 to 25°C for 1 to 2 hours. The reaction with the Grignard reagent iε carried out by cooling a solution of the compound of Formula XII in a εuitable solvent (e.g., THF, diethyl ether, etc.) to between -10 and -20°C, preferably to approximately -15°C and then adding the suεpenεion containing the Grignard reagent, cooled to approximately the εame temperature, and allowing the reaction to proceed at 0 to 15°C, preferably at approximately 10°C, for 1 to 2 hours. Deprotection can be effected by any means which removes the protective group and gives the desired unprotected alkanone in good yield. The reaction with the unprotected alkanone is carried out under nitrogen with 3 to 6 equivalents, preferably 3 to 4 equivalents, of NHR 5 R 6 in a suitable solvent (e.g., DMF, NMP, etc.) at 55 to 85°C, preferably at 55 to 60°C, and requires 4 to 8 hourε. The preparation of a compound of Formula I by the proceεε characterized above iε deεcribed in Example 14. Compoundε of Formula XII can be prepared by reacting a compound of Formula III with a εuitable protecting agent. A detailed description of the techniques applicable to protective groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. For example, compounds of Formula XII in which the protective groups are trimethylsilyl can be prepared by reacting a compound of Formula III with chlorotrimethylεilane. The reaction iε carried out in the presence of strong base (e.g., tert-butylmagnesium chloride, lithium bis(trimethylsilyl)amide (LiHMDS) , etc.) under nitrogen in a suitable solvent (e.g., THF, ether, etc.) at -15 to 15°C, preferably at approximately 10 β C, and requireε 15 to 30 minutes. Deprotection of a compound of Formula XII in which the protective groups are trimethylsilyl can be effected with acid (e.g., hydrochloric acid, trifluoroacetic acid, etc.) . A method for making compounds of Formula I in which R 4 iε a group of Formula (a) is depicted by the following Reaction Scheme V: REACTION SCHEME V ». DirROTCCTIΦ* in which each P is a protective group and R 1 , R 2 , R 3 , R 3 and R 6 are as defined in the Summary of the Invention. Compounds of Formula I in which R 4 iε a group of Formula (a) can be prepared by reacting the acid addition εalt of a corresponding compound of Formula II (Formula II(a) ) with a compound of Formula XIII in the presence of a strong base (e.g., LiHMDS, sodium bis (trimethylsilyl)amide, lithium diiεopropylamide, preferably LiHMDS) and then deprotecting. The reaction between the compoundε of Formulae II (a) and XIV can be carried out by cooling a mixture containing the compound of Formula II (a) in a εuitable solvent (e.g., THF, ethylene glycol dimethyl ether, diethyl ether, etc.) to between 10 and 30°C, preferably to approximately 15°C; adding a minimum of 3 equivalents of the strong base and allowing 0.5 to 2 hours at 10 to 30°C, preferably at approximately 20°C; cooling the mixture to between 0 and 10°C, preferably to approximately 5°C; and then adding the compound of Formula XIII and allowing the reaction to proceed at 40 to 55°C for approximately 4 hour . Deprotection can be effected by any means which removes the protective group and gives the deεired unprotected product in good yield. A εuitable protective group for the compound of Formula XIII iε trimethylεilyl which can be readily removed with acid. The preparation of a compound of Formula I by the proceεs characterized above is described in Example 15. Compounds of Formula XIII can be prepared by reacting a corresponding benzoic acid with methanol in the presence of thionyl chloride and then adding the protective groups. The reaction with the benzoic acid is carried out at 0 to 25°C, preferably at approximately 15°C, and requireε 1 to 4 hours. The protection can be carried out with chlorotrimethylεilane in the presence of strong base (e.g., tert-butylmagnesium chloride, LiHMDS, etc.) in a suitable solvent. Additional Processes: Compounds of Formula I in which R 3 is (C w )alkyloxy or phenyl(C M )alkyloxy can be prepared by demethylating a compound of Formula I in which R 3 is methoxy, and then alkylating with a compound of the formula L-R 22 in which R 22 is (C-_,)alkyl or phenyl (C )alkyl (wherein the phenyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, (C M )alkyl, (C M )alkyloxy, nitro, amino, aminocarbonyl, (C )alkylamino, di (C )alkylamino, (C.^alkanoylamino and 3,4-methylenedioxy) . The demethylation is carried out by standard methods with an appropriate demethylating agent (e.g., boron tribromide, boron trichloride, etc.) and in an aprotic solvent (e.g., methylene chloride, dichloroethane, etc.) or with acid (e.g., aqueous hydrobromic acid) to form the corresponding 2-hydroxyphenylalkan-l-one. The alkylation is carried out in the presence of potassium carbonate in a suitable solvent (e.g., methyl ethyl ketone (MEK) , DMF, ethanol, THF, etc., preferably MEK) at 40 to 200°C. The preparation of a compound of Formula I by the above process is described in Example 12. The compounds of Formula I wherein p iε 1 (compounds of Formula I in the form) can be prepared by oxidizing a compound of Formula I in which p iε 0. The oxidation iε carried out at a reaction temperature of approximately 0°C with an appropriate oxidizing agent and in a εuitable inert, organic solvent. Suitable oxidizing agentε include hydrogen peroxide or peroxy acidε εuch aε trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, and m-chloroperoxybenzoic acid. Suitable εolventε include halogenated hydrocarbon , e.g., methylene chloride, and alcoholε. Alternatively, the compoundε of Formula I wherein p iε 1 may be prepared using tv-oxide derivatives of the starting materials or intermediates. Compounds of Formula I in which p iε 0 can be prepared by reducing a compound of Formula I wherein p iε 1. The reduction is carried out under standard conditions with an appropriate reducing agent in a εuitable εolvent. The mixture iε occaεionally agitated while the reaction temperature is gradually increased over a range of 0°C to 80°C. Appropriate reducing agentε include εulfur, εulfur dioxide, triarylphoεphines (e.g., triphenylphosphine) , alkali borohydrides (e.g., lithium borohydride, εodium borohydride, etc.), phosphorus trichloride and tribromide. Suitable solvents include acetonitrile, ethanol or aqueous dioxane. Compounds of Formula I may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable base addition εaltε of compoundε of Formula I may be prepared by reacting the free acid forms of compounds of Formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application. Alternatively, the salt forms of the compounds of Formula I may be prepared using salts of the starting materials or intermediates. The free acid or free baεe formε of the compoundε of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, compounds of Formula I in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.) . Compounds of Formula I in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc) . In summary, the proceεεes for preparing the compoundε of thiε invention are: (A) for the preparation of a compound of Formula I, reacting, in the preεence of a strong baεe, a compound of Formula II: I I or the protected derivative thereof, in which R 4 iε aε defined in the Summary of the Invention; with a compound of Formula III: in which each R 1 , R 2 and R 3 are aε defined in the Summary of the Invention; acidifying; decarboxylating; and when neceεsary removing any protective groups; or (B) for the preparation of a compound of Formula I in which R 2 is hydrogen and R 4 is a group of Formula (a) , reacting, in the presence of a Lewis acid, a compound of Formula V: in which P is a protective group and R 1 is halo, with a compound of Formula VI: V ,1» (CH,), VI in which R 18 is halo or hydroxy and R 19 is halo and n is 3, 4 or 5; alkylating with a compound of the formula L-R 3 in which L iε a leaving group and R 3 is as defined above; reacting with a compound the formula HNR 5 R 6 , or the N-oxide thereof, in which R 3 and R 6 are aε defined above; and deprotecting; or (C) for the preparation of a compound of Formula I in which R 4 iε a group of Formula (b) wherein p is 0 and q iε 2, reacting a compound of Formula VIII: VI II in which R 1 , R 2 and R 3 are aε defined in the Summary of the Invention; with a compound of Formula IX: IX in which R 7 iε as defined in the Summary of the Invention; dehydrating; and then hydrogenating; or (D) for the preparation of a compound of Formula I in which R 4 is a group of Formula (a) , treating a compound of Formula XI: Br ^ ,CI (CH 8 ) B XI in which n is as defined in the Summary of the Invention, with magnesium to give a corresponding Grignard reagent, reacting the Grignard reagent with a compound of Formula XII: in which each P iε a protective group and R 1 , R 2 and R 3 are aε defined in the Summary of the Invention, deprotecting and then reacting with a compound of the formula NHR 3 R 6 ; or (E) for the preparation of a compound of Formula I in which R 4 iε a group of Formula (a) , reacting, in the preεence of a εtrong baεe, a compound of Formula II (a) : IK*) in which R 5 and R 6 is as defined in the Summary of the Invention, with a compound of Formula XIII: XIII in which each P is a protective group and R 1 , R 2 and R 3 are as defined in the Summary of the Invention; or (F) optionally alkylating a compound of Formula I in which R 4 is a group of Formula (b) and R 7 is hydrogen with a compound of the formula L-R 20 in which L iε leaving group and R 20 is (C,^)alkyl, (C M )alkenyl, phenyl (C,^)alkyl (wherein the phenyl is optionally substituted with one to three subεtituents independently selected from (C M )alkyloxy, methylenedioxy, ethylenedioxy or halo) or L-(C__ 2 ) Z R 12 (wherein z and R 12 are as defined in the Summary of the Invention) to give a compound of Formula I in which R 4 iε a group of Formula (b) wherein R 7 iε not hydrogen; or (G) optionally alkylating a compound of Formula I in which R 4 iε a group of Formula (b) and R 7 is hydrogen with a compound of the formula X-R 21 in which X is azacycloprop-1-yl and R 21 is -C(0)R 14 , -S0 2 R 14 , -S0 2 I R 13 or - C0NR 14 R 13 (wherein R 14 and R 13 are aε defined in the Summary of the Invention) to give a compound of Formula I in which R 4 iε a group of Formula (b) wherein R 7 iε -CH 2 CH 2 NHC(0)R 14 , -CH J CH J NHSO^ 14 , -CH 2 CH 2 NHS0 2 NR 1 R 13 or -CH 2 CH 2 NHC0NR 1 R 13 ; or (H) optionally demethylating a compound of Formula I in which R 3 iε methoxy, and then alkylating with a compound of the formula L-R 22 in which R 22 iε (C 2 -,)alkyl or phenyl (C M )alkyl (wherein the phenyl iε optionally εubεtituted with one to three substituents independently selected from halo, hydroxy, (C )alkyl, (C )alkyloxy, nitro, amino, aminocarbonyl, (C M )alkylamino, di (C M )alkylamino, (C )alkanoylamino and 3,4-methylenedioxy) to give a compound of Formula I in which R 3 is (C w )alkyloxy or phenyl (C M )alkyloxy (wherein the phenyl is optionally substituted aε defined in the Summary of the Invention) ; or (I) optionally oxidizing a compound of Formula I in which p iε 0 to give a compound of Formula I in which p is 1; or (J) optionally reducing a compound of Formula I in which p iε 1 to give a compound of Formula I in which p iε 0; or (K) optionally reacting the correεponding non-εalt form of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid or base to give a pharmaceutically acceptable salt; or (L) optionally reacting the correεponding acid addition salt or base addition salt form of a compound of Formula I with a suitable base or acid, respectively, to give the free acid or free baεe. In any of the above laεt step processes, a reference to Formulae I, II, 11(a), III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII refers to such formulae wherein R 1 , R 2 , R 3 , R 4 , R 3 and R 7 are as defined in their broadest definitions set forth in the Summary of the Invention, with the processes applying particularly well to the presently preferred embodiments. Examples: EXAMPLE 1 3- [1- (tert-Butoxycarbonyl)pipβridin-4-yl]propionic acid The following is the preparation of a protected derivative of a compound of Formula II in which R 4 is a group of Formula (b) wherein q iε 2. Step (a) 4-Hydroxymethylpiperidine (27.0 g, 262 mmol) and di- ert-butyldicarbonate (51.2 g, 235 mmol) were diεεolved in THF (300 mL) and the εolution was stirred 12 hours at room temperature. The mixture was concentrated in vacuo and the residue was diεεolved in ether. The ether εolution waε waεhed with water and then with brine, and dried over sodium εulfate. Evaporation of the εolventε gave a reεidue (51.0 g) as an oil. The oil residue was dissolved in pyridine (200 mL) and the solution waε cooled to 0°C. p-Toluenesulfonyl chloride (47.5 g, 250 mmol) was then added to the solution and the mixture was εtored at 5°C for 12 hours. The mixture waε poured into water and extracted into ethyl acetate. The ethyl acetate extract waε washed with 5% HCl, with water, and then with brine. The ethyl acetate was then dried over sodium sulfate and then evaporated. Cryεtallization from ethyl acetate-hexane gave 1- (tert-butoxycarbonyl) - 4- [ (p-tolueneεulfonyloxy)methyl] -piperidine (50 g, 136 mmol), m.p. 71-72°C. Step (b) Diethyl malonate (10.4 g, 65 mmol) waε added to a εolution of sodium ethoxide (4.42 g, 65 mmol) in ethanol (75 mL) . 1- (tert-Butoxycarbonyl) - 4- [ (p-tolueneεulfonyloxy)methyl]piperidine (25 g, 68 mmol), prepared aε in Example 1, Step (a) , was added and the mixture was heated at reflux for 4 hourε. The mixture was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water and then brine, dried over εodium εulfate, and evaporated. Purification of the reεidue by silica gel chromatography (25% ethyl acetate-hexane) gave 1- (tert-butoxycarbonyl) -4- [2,2-di (ethoxycarbonyl)ethyl]piperidine (16 g, 45 mmol) as an oil. Step (c) 1- (tert-Butoxycarbonyl) -4- [2,2-di (ethoxycarbonyl)ethyl]piperidine (12.2 g, 34 mmol), prepared as in Example 1, Step (b) , and potassium hydroxide (4.2 g, 75 mmol) were combined in ethanol (10 mL) , THF (20 mL) , and water (50 mL) and the mixture was heated at reflux for 3 hours. The mixture waε cooled and washed with ether, acidified with sulfuric acid, and extracted into ether. The ether was dried over sodium sulfate and evaporated. Crystallization of the residue from ether gave 1- (tert-butoxycarbonyl) -4- [2,2-di(carboxy)ethyl]piperidine (8.5 g, 28 mmol) which was heated in an oil bath to 165°C until evolution of C0 2 ceased (approximately 10 minutes) . The residue was cooled and upon crystallization gave 3- [1- (tert-butoxycarbonyl)piperidin-4-yl]propionic acid (7.2 g, 28 mmol), m.p. 81-83°C. EXAMPLE 2 it-Methox --.-me hyl-4-amino-5-chloro-2-methoxybenzamide The following is the preparation of a compound of Formula III in which R 1 is chloro and R 3 is methoxy. 4-Amino-5-chloro-2-methoxybenzoic acid (10.1 g, 50 mmol) was disεolved in DMF (50 mL) . Carbonyldiimidazole (8.9 g, 55 mmol) waε added to the solution and the mixture was stirred for 15 minutes. Triethylamine (7 mL, 5.1 g, 50 mmol) and N, O-dimethylhydroxylamine hydrochloride (6.3 g, 65 mmol) were added and the mixture waε εtirred for 12 hourε. The mixture waε then diluted with water and extracted into ethyl acetate. The ethyl acetate extract waε washed with 5% HCl, with water, and then with brine. The extract was dried over sodium sulfate and then evaporated. Crystallization from ethyl acetate gave t7-methoxy-i\t-methyl-4 -amino-5 - chloro-2-methoxybenzamide (10 g, 41 mmol), m.p. 134-135°C. EXAMPLE 3 1- {4-A__ino-5-chloro-2-methoxyphenyl) - 3- (l-pipβridin-4-yl)propan-1-one The following is the preparation of a compound of Formula I in which R 1 iε chloro, R 3 iε methoxy, R 4 is a group of Formula (b) in which p is 0, q is 2, and R 7 iε hydrogen. Step (a) 3- [1- ( ert-Butoxycarbonyl)piperidin-4-yl]propionic acid (4.6 g, 18 mmol) , prepared as in Example 1, was dissolved in HMPA (10 mL) and THF (10 mL) , and this solution waε added to a -20° solution of lithium diisopropylamide (60 mmol) . The mixture waε warmed to 0°C, stirred for 30 minutes, and then cooled to -40°C. _.-Metho-cy-.W-methyl-4-amino-5-chloro- 2-methoxybenzamide (4.9 g, 20 mmol), prepared as in Example 2, was disεolved in HMPA (10 mL) and THF (10 mL) and thiε solution was added to the mixture. The mixture waε allowed to warm to 0°C over 1 hour, then diluted with water, waεhed with ether, acidified with hydrochloric acid, and extracted into methylene chloride. The methylene chloride extract waε concentrated in vacuo and the residue was heated in an oil bath to 140°C for 30 minutes. The mixture waε cooled, partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with 5% εodium hydroxide and then brine, dried over εodium εulfate, and evaporated. Purification by silica gel chromatography (40% ethyl acetate-hexane) gave 1- (4-amino-5-chloro-2-methoxyphenyl) - -SI¬ S' [1- ( ert-butoxycarbonyl)piperidin-4-yl] -propan-1-one (1.5 g, 3.8 mmol), m.p. 133-134°C. Step (b) 1- (4-Amino-5-chloro-2-methoxyphenyl) -3- [1- (tert-butoxycarbonyl) - piperidin-4-yl]propan-1-one (1.5 g, 3.8 mmol) was diεεolved in methylene chloride (20 mL) and trifluoroacetic acid (5 mL) waε added to the εolution. After 30 minutes the εolution waε waεhed with aqueouε ammonium hydroxide, and dried over εodium εulfate. Evaporation of the εolventε gave 1- (4-amino-5-chloro-2-methoxyphenyl) -3- (piperidin-4-yl) -propan-1-one (1.1 g, 3.8 mmol), m.p. 138-140°C. EXAMPLE 4 1- (4-AiQino-5 -chloro-2-inethoxyphenyl) - 5- (piperidin-l-yl) pentan- l-one The following iε the preparation of a compound of Formula I in which R 1 iε chloro, R 3 iε methoxy, and R 4 iε a group of the Formula (a) wherein n is 4, p is 0, and R 3 and R 6 together are piperidin-1-yl. Step (a) 27-Acetyl-2-chloro-5-methoxyaniline (10.0 g, 50 mmol), aluminum chloride (13.3 g, 100 mmol), and 5-chloropentanoyl chloride (11.7 g, 75 mmol) were combined in ethylene dichloride (100 mL) and the mixture waε stirred at room temperature and under nitrogen for 7 days. The mixture waε then poured onto crushed ice and extracted into methylene chloride. The methylene chloride extract was washed with water and then dried. The solvent was evaporated in vacuo. Crystallization of the residue from ethyl acetate /hexane gave 1- (4-acetylamino-5-chloro-2-hydroxyphenyl) - 5-chloropentan-l-one (10.18 g, 35.1 mmol), m.p. 126-128°C. Proceeding as in Example 4, Step (a), but replacing 1,5-dichloro- pentan-l-one with 4-chlorobutyryl chloride, gave 1- (4-acetylamino-5-chloro- 2-hydroxyphenyl) -4-chlorobutan-l-one, m.p. 103-106°C. Proceeding as in Example 4, Step (a), but replacing 1,5-dichloro- pentan-1-one with 1,5-dibromopentan-l-one and _v"-acetyl-2-chloro- 5-methoxyaniline with W-acetyl-2-bromo-5-methoxyaniline, gave 1- (4-acetylamino-5-bromo-2-hydroxyphenyl) -5-bromopentan-l-one. Step (b) 1- (4-Acetylamino-5-chloro-2-hydroxyphenyl) -5-chloropentan-l-one (1.07 g, 3.5 mmol), potassium carbonate (1.38 g, 10.0 mmol) and iodomethane (0.62 mL, 10.0 mmol) were combined in methyl ethyl ketone (20 mL) and stirred at reflux temperature for 4 hours, 15 minutes. The mixture waε partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed in brine, dried over sodium sulfate, and then evaporated to leave a solid residue. Crystallization of the residue from ethyl acetate-hexaneε gave 1- (4-acetylamino-5-chloro-2-methoxyphenyl) -5-chloro-pentan-l-one (0.720 g, 2.37 mmol), m.p. 98-100°C. Proceeding aε in Example 4, Step (b) , but replacing 1- (4-acetylamino- 5-chloro-2-hydroxphenyl) -5-chloropentan-l-one with 1- (4-acetylamino-5- chloro-2-hydroxyphenyl) -4-chlorobutan-l-one, gave 1- (4-acetylamino-5-chloro-2-methoxyphenyl) -4-chlorobutan-l-one as an oil. Proceeding aε in Example 4, Step (b) , but replacing iodomethane with 4-methoxybenzylchloride, gave 1- [4-acetylamino-5-chloro- 2- (4-methoxybenzyloxy) -phenyl] -5-chloropentan-l-one, m.p. 147-149°C. Proceeding aε in Example 4, Step (b) , but replacing iodomethane with 3,4-dimethoxybenzylchloride, gave 1- [4-acetylamino-5-chloro- 2- (3,4-dimethoxy-benzyloxy)phenyl] -5-chloropentan-l-one, m.p. 147°C. Proceeding as in Example 4, Step (b) , but replacing iodomethane with 3,5-dimethoxybenzylchloride, gave 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxy-benzyloxy)phenyl] -5-chloropentan-l-one, m.p. 135-137°C. Proceeding as in Example 4, Step (b) , but replacing iodomethane with 3,5-dimethoxybenzylchloride and 1- (4-acetylamino-5-chloro-2-hydroxyphenyl) - 5-chloropentan-l-one with l- (4-acetylamino-5-bromo-2-hydroxyphenyl) - 5-bromo-pentan-l-one, gave 1- [4-acetylamino-5-bromo- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-bromopentan-1-one. Proceeding aε in Example 4, Step (b) , but replacing iodomethane with 3,4-methylenedioxybenzylchloride, gave 1- [4-acetylamino-5-chloro- 2- (3,4-methylenedioxybenzyloxy)phenyl] -5-chloropentan-l-one, m.p. 132- 134°C. Proceeding as in Example 4, Step (b) , but replacing iodomethane with 2- (4-methoxyphenyl) -1-iodoethane, gave 1-{4-acetylamino-5-chloro- 2- [2- (4-methoxyphen)ethoxy]phenyl}-5-chloropentan-l-one, m.p. 108-110°C. Proceeding as in Example 4, Step (b) , but replacing iodomethane with 2- (3,4-dimethoxyphenyl) -1-iodoethane, gave 1-{4-acetylamino-5-chloro- 2- [2- (3,4-dimethoxyphen)ethoxy]phenyl}-5-chloropentan-l-one. Step (c) 1- (4-Acetylamino-5-chloro-2-methoxyphenyl) -5-chloropentan-l-one (0.72 g, 2.26 mmol), sodium iodide (0.15 g, 0.1 mmol), and piperidine (1.72 g, 20 mmol) were combined in DMF (8.0 mL) and the mixture waε heated to 80°C for 4.5 hourε. Water waε then added to form a precipitate. Filtration gave 1- (4-acetylamino-5-chloro-2-methoxyphenyl) - 5- (piperidin-l-yl)pentan-l-one (0.8 g, 2.18 mmol), m.p. 74-75°C. 1- (4-Acetylamino-5-chloro- -methoxyphenyl) - 5- (piperidin-l-yl)pentan-l-one waε diεεolved in 2N hydrochloric acid (25 mL) and the εolution waε εtirred for 30 minutes. The solution was cooled in an ice bath to form a precipitate. The precipitate was collected by filtration and washed with water. Drying in a vacuum oven at 70°C gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (piperidin-l-yl)pentan-l-one hydrochloride (0.65 g, 2 mmol), m.p. 220-221°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with l- (4-acetylamino- 5-chloro-2-methoxyphenyl) -4-chlorobutan-l-one and piperidine with diethylamine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 4-diethylaminobutan-l-one hydrochloride, m.p. 145-150°C. Proceeding aε in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- (4-acetylamino-5-chloro-2-methoxyphenyl) -4-chlorobutan-l-one and piperidine with pyrrolidine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 4- (pyrrolidin-l-yl)butan-1-one hydrochloride, m.p. 221-224°C. Proceeding aε in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- (4-acetylamino-5-chloro-2-methoxyphenyl) -4-chlorobutan-1-one, gave 1- (4-amino-5-chloro-2-methoxy-phenyl) -4- (piperidin-l-yl)butan-l-one hydrochloride, m.p. 235-238°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with dimethylamine, gave 1- (4-amino-5-chloro-2-methoxyp__enyl) -5-dimethy1amino- pentan-1-one hydrochloride, m.p. 219-220°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with diethylamine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5-diethylamino- pentan-1-one hydrochloride, m.p. 178-179°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with di(prop-1-yl)amine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5-di (prop-1- yl) -aminopentan-1-one hydrochloride, m.p. 162-165°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with pyrrolidine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (pyrrolidin-l-yl) - pentan-l-one hydrochloride, m.p. 203-205°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with 4-methylpiperidine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (4-methyl- piperidin-1-yl)pentan-l-one hydrochloride, m.p. 195-197°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with 4,4-dimethylpiperidine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 5- (4,4-dimethylpiperidin-l-yl)pentan-l-one hydrochloride, m.p. 239-241°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with 4-ethylpiperidine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (4-ethyl- piperidin-l-yl)pentan-l-one hydrochloride, m.p. 197-198°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with 4- (prop-1-yl)piperidine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 5- [4- (prop-l-yl)piperidin-l-yl]pentan-l-one hydrochloride, m.p. 212-213°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with 4-aminocarbonylpiperidine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 5- (4-aminocarbonylpiperidin-1-yl)pentan-l-one hydrochloride, m.p. 230-235°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with 4-hydroxypiperidine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 5- (4-hydroxy-piperidin-l-yl)pentan-l-one hydrochloride, m.p. 205-207°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with 4-methoxypiperidine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 5- (4-methoxy-piperidin-l-yl)pentan-l-one hydrochloride, m.p. 193-195°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with 4- (methylεulfonyl)aminopiperidine, gave 1- (4-amino-5-chloro- 2-methoxyphenyl) -5- [4- (methylεulfonyl)aminopiperidin-l-yl]pentan-l-one hydrochloride, m.p. 245-246°C. Proceeding aε in Example 4, Step (c) , but replacing piperidine with 4- (methylεulfonyl)aminomethylpiperidine, gave 1- (4-amino-5-chloro- 2-methoxy-phenyl) -5- [4- (methylsulfonyl)aminomethylpiperidin-1-yl]pentan-l- one hydrochloride, m.p. 231-232°C. Proceeding as in Example 4, Step (c) , but replacing piperidine with 4-phenylpiperidine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (4-phenyl- piperidin-l-yl)pentan-l-one hydrochloride, m.p. 257-259°C. Proceeding as in Example 4, Step (c) , but replacing piperidine with morpholine, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (morphol-1-yl) - pentan-l-one hydrochloride, m.p. 229-231°C. Proceeding as in Example 4, Step (c) , but replacing piperidine with azacycloheptane, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (azacyclo- hept-1-yl)pentan-l-one hydrochloride, m.p. 203-205°C. Proceeding as in Example 4, Step (c) , but replacing piperidine with 3-azabicyclo[2.2.l]heptane, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 5- (3-azabicyclo[2.2.l]hept-3-yl)pentan-l-one hydrochloride, m.p. 158-160°C. Proceeding as in Example 4, Step (c) , but replacing 1- ( -acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- [4-acetylamino-5-chloro-2- (4-methoxybenzyloxy)phenyl] - 5-chloropentan-l-one, gave 1- [4-amino-5-chloro- 2- (4-methoxybenzyloxy)phenyl] -5- (piperidin-l-yl)pentan-l-one hydrochloride, m.p. 229-230°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- [4-acetylamino-5-chloro-2- (3,4-dimethoxy)benzyloxyphenyl] -5-chloro- pentan-l-one, gave 1- [ -amino-5-chloro-2- (3,4-dimethoxybenzyloxy)phenyl] - 5- (piperidin-l-yl)pentan-l-one, m.p. 125-127°C. Proceeding aε in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- [4-acetylamino-5-chloro- 2- (3,4-methylenedioxybenzyloxy)phenyl] -5-chloropentan-l-one, gave 1- [4-amino-5-chloro-2- (3,4-methylenedioxybenzyloxy)phenyl] - 5- (piperidin-l-yl)pentan-l-one, m.p. 120-122°C. Proceeding aε in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- [4-acetylamino- 5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-l-one and piperidine with dimethylamine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-dimethylaminopentan-1-one hydrochloride, m.p. 221-224°C. Proceeding aε in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 5-chloropentan-l-one and piperidine with diethylamine, gave 1- [4-amino- 5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] -5-diethylaminopentan-l-one, m.p. 105-107°C. Proceeding aε in Example 4, Step (c) , but replacing 1- ( -acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino- 5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloro-pentan-l-one and piperidine with pyrrolidine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5- (pyrrolidin-l-yl)pentan-l-one, m.p. 125-127°C. Proceeding aε in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-l-one, gave 1- [4-amino- 5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] -5- (piperidin-l-yl)pentan-l-one, m.p. 128-130°C. Proceeding aε in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- (4-acetylamino- 5-bromo-2- (3,5-dimethoxy)benzyloxyphenyl] -5-bromopentan-l-one, gave 1- (4- amino-5-bromo-2- (3,5-dimethoxy)benzyloxyphenyl] -5- (piperdin-l-yl)pentan-l- one hydrochloride, m.p. 238-239°C. Proceeding aε in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-l-one and piperidine with 4-methylpiperidine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5- (4-methylpiperidin-l-yl)pentan-l-one, m.p. 136-137°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [ -acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-l-one and piperidine with 4- (prop-1-yl)piperidine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy) -phenyl] -5- [4- (prop-1-yl)piperidin-1- yl]pentan-l-one, m.p. 119-120°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-1-one and piperidine with 4,4-dimethylpiperidine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy) -phenyl] -5- (4,4-dimethylpiperidin-l- yl)pentan-l-one, m.p. 135-136°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino- 5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-1-one and piperidine with 4-hydroxypiperidine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy) -phenyl] -5- (4-hydroxypiperidin-1-yl)pentan-l-one hydrochloride, m.p. 220-222°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-1-one and piperidine with 4- (2-hydroxyethyl)piperidine, gave 1- [4-amino-5-chloro-2- (3,5-dimethoxy¬ benzyloxy)phenyl] -5- [4- (2-hydroxyethyl)piperidin-l-yl]pentan-l-one hydrochloride, m.p. 180-183°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloro- pentan-1-one and piperidine with 4-methoxypiperidine, gave 1- [4-amino- 5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] -5- (4-methoxypiperidin-l- yl)pentan-l-one hydrochloride, m.p. 195-196°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-l-one and piperidine with 4-aminocarbonylpiperidine, gave 1- [4-amino-5-chloro-2- (3,5- dimethoxybenzyloxy) -phenyl] -5- (4-aminocarbonylpiperidin-l-yl)pentan-l-one hydrochloride, m.p. 207-209°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-l-one and piperidine with 4- (aminocarbonyl)aminopiperidine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxy-benzyloxy)phenyl] -5- [4- (aminocarbonyl)aminopiperidin-1- yl]pentan-l-one hydrochloride, m.p. 220-224°C. Proceeding aε in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-1-one and piperidine with 4- (aminocarbonyl)aminomethylpiperidine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5- [4- (aminocarbonyl)aminomethyl- piperidin-1-yl]pentan-l-one hydrochloride, m.p. 130-135°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-1-one and piperidine with 4- (methylsulfonyl)aminopiperidine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxy-benzyloxy)phenyl] - 5- [4- (methylsulfonyl)aminopiperidin-1-yl]pentan-l-one hydrochloride, m.p. 240-245°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-l-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-1-one and piperidine with 4- (methylsulfonyl)aminomethylpiperidine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5- [4- (methylsulfonyl)aminomethyl- piperidin-l-yl]pentan-l-one hydrochloride, m.p. 211-213°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-1-one and piperidine with 4- [2- (methylsulfonyl)aminoethyl]piperidine, gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-{4- [2- (methylsulfonyl)aminoethyl] - piperidin-l-yl}pentan-l-one hydrochloride, m.p. 205-206°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-1-one and piperidine with 4-phenylpiperidine, gave 1- [4-amino-5-chloro-2- (3,5- dimethoxybenzyloxy)phenyl] -5- (4-phenylpiperidin-l-yl)pentan-l-one hydrochloride, m.p. 237-239°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1- [4-acetylamino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -5-chloropentan-1-one and piperidine with azacycloheptane, gave 1- [4-amino-5-chloro-2- (3,5- dimethoxybenzyloxy)phenyl] -5- (azacyclohept-l-yl)pentan-l-one, m.p. 137-139°C. Proceeding as in Example 4, Step (c) , but replacing 1- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1-{4-acetylamino-5-chloro- 2- [2- (4-methoxyphen)ethoxy]phenyl}-5-chloropentan-1-one, gave 1-{4-amino- 5-chloro-2- [2- (4-methoxyphen)ethoxy]phenyl}-5- (piperidin-1-yl)pentan-l-one, m.p. 211-212°C. Proceeding aε in Example 4, Step (c) , but replacing 1- (4-acetylamino- -38 - 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with l-{4-acetylamino-5-chloro- 2- [2- (3,4-dimethoxyphen)ethoxy]phenyl}-5-chloropentan-1-one, gave l-{4-amino-5-chloro-2- [2- (3,4-dimethoxyphen)ethoxy]phenyl}- 5- (piperidin-1-yl)pentan-l-one, m.p. 224-225°C. Proceeding aε in Example 4, Step (c) , but replacing l- (4-acetylamino- 5-chloro-2-methoxyphenyl) -5-chloropentan-1-one with 1-{ -acetylamino-5-chloro- 2- [2- (4-methoxyphen)ethoxy]phenyl}-5-chloropenta -1-one and piperdine with 4-methylpiperidine, gave l-{4-amino-5-chloro-2- [2- (4-methoxyphen)ethoxy] - phenyl}-5- (4-methylpiperidin-l-yl)pentan-l-one hydrochloride, m.p. 226-228°C. EXAMPLE 5 4' -Amino-5' -chloro-2' -mβthoxyacetophenonβ The following iε the preparation of a compound of Formula VIII in which R 1 is chloro, R 2 is hydrogen and R 3 is methoxy. tv'-Methoxy-tv'-methyl -4 -__mino-5-chloro-2 -methoxybenzamide (24.4 g, 100 mmol) was dissolved in THF (400 mL) and the solution waε cooled to -40°C. Methyl-lithium in ether (143 mL, 4.4 g, 200 mmol) ) was added and the mixture was allowed to warm to 0°C. Aqueous hydrochloric acid was added and the mixture was extracted into ethyl acetate. The extract waε washed with brine, dried over εodium sulfate, and evaporated to leave a solid. Crystallization from ethyl acetate-hexane gave 4'-amino-5' -chloro-2' - methoxyacetophenone (15.0 g, 75 mmol), m.p. 114-116°C. Proceeding as in Example 5, but replacing W-methoxy-W-methyl-4-amino- 5-chloro-2-methoxybenzamide with W-methoxy-N-methyl-4-amino-5-chloro- 2,3-ethylenedioxybenzamide gave 4-amino-5-chloro-2,3-ethylenedioxyphenyl- acetophenone, m.p. 133-135 β C. Proceeding as in Example 5, but replacing W-methoxy-_v " -methyl-4-__mino- 5-chloro-2-methoxybenzamide with W-methoxy-W-methyl-4-amino-5-chloro- 2,3-dimethoxybenzamide gave 4-amino-5-chloro-2,3- dimethoxyphenylacetophenone, m.p. 75-78°C. EXAMPLE 6 4* -Amino-5' -chloro-2'3 ' -ethylenedioxyacetophenone The following iε the preparation of a compound of Formula VI in which R 1 iε chloro and R 2 and R 3 are together ethylenedioxy. Step (a) A εolution of 1,4-benzodioxan (8.4 M, 25 mL, 0.21 mol) in 15 mL of acetic acid waε treated with chlorine gas at 10 to 20°C giving a yellow precipitate. The precipitate was isolated by filtration and waεhed with water. Cryεtallization of the precipitate from ethanol gave 6, 7-dichloro- 1,4-benzodioxane (25.5 g, 0.124 mol), m.p. 147-148°C. Step (b) A mixture of 6,7-dichloro-l,4-benzodioxane (10.25 g, 0.05 mol), acetyl chloride (13.5 M, 5 mL, 0.0675 mol) and aluminum chloride (10 g, 0.075 mol) in 200 mL of 1,2-dichloroethane waε stirred under nitrogen for 24 hourε. The mixture was poured into approximately 500 mL of ice/dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride extract were washed with sodium bicarbonate (lx) , water (lx) and brine (lx) and then dried over sodium sulfate. The methylene chloride was filtered and concentrated by rotary evaporation. Purification of the residue by column chromatography (silica 230-400 mesh; 15% ethyl acetate/hexane) gave 5,6-dichloro-2,3-ethylenedioxy-acetophenone (8.1 g, 0.033 mol), m.p. 83-86°C. Step (c) 5' ,6' -Dichloro-2' ,3 ' -ethylenedioxyacetophenone (8.5 g, 0.0344 mol) was added in portions to 34.5 mL of stirring fuming nitric acid at a rate such that the temperature of the reaction mixture remained below 10°C. The mixture was stirred for an additional 10 minutes at 5°C and then poured onto 250 g of crushed ice giving yellow precipitate. The precipitate was iεolated by filtration and washed with water. Drying gave 5' , 6' -dichloro- 2' ,3 ' -ethylenedioxy-4 ' -nitroacetophenone (8.9 g, 0.0341 mol), m.p. 181-182°C. Step (d) A mixture of 5' ,6' -dichloro-2' ,3 ' -ethylenedioxy-4 ' -nitroacetophenone (2 g, 7.63 mmol) and 10% palladium on carbon (800 mg) in 17 mL of 15% εodium hydroxide and 160 mL of ethanol hydrogenated at 57 psi for 7 hours. The mixture waε filtered and concentrated by rotary evaporation and the reεidue was stirred into water. Drying gave 4'-amino- 2' ,3 ' -ethylenedioxyacetophenone (970 mg, 5.04 mmol), m.p. 135-136°C. Step (e) A εolution of 4 ' -amino-2',3' -ethylenedioxyacetophenone (310 mg, 1.60 mmol) in 2.3 mL of pyridine under nitrogen was cooled in an ice/water bath and 6.9 mL of acetic anhydride waε added drop-wiεe. The mixture waε allowed to warm to room temperature and then εtirred for 16 hours. The mixture waε concentrated by rotary evaporation and the reεidue waε εtirred into water. The reεidue was isolated by filtration and waεhed with water. Drying gave 2' ,3' -ethylenedioxy-4' - (methylcarbonylamino)acetophenone (289 mg, 1.23 mmol), m.p. 142-144°C. Step (f) A εolution of 2' ,3' -ethylenedioxy-4' - (methylcarbonylamino)acetophenone (250 mg, 1.06 mmol) in 6 mL of dimethylformamide under nitrogen waε cooled in an ice/water bath and tv"-chloroεuccinimide (156 mg, 1.17 mmol) was added. The mixture was allowed to warm to room temperature and then heated at 55°C for 1.5 hourε. The mixture waε then cooled to room temperature and εtirred for 16 hours. The mixture was concentrated by rotary evaporation and the residue was εtirred into water. The residue was isolated by filtration and washed with water. Drying gave 5' -chloro-2' ,3' -ethylenedioxy-4' - (methylcarbonylamino) - acetophenone (170 mg, 0.69 mmol), m.p. 181-182°C. Step (g) A mixture of 5' -chloro-2' ,3' -ethylenedioxy-4' - (methylcarbonylamino) - acetophenone (152 mg, 0.56 mmol) and sodium hydroxide (4N, 1.4 mL, 5.6 mmol) in 5 mL of methanol waε heated at reflux for 3.5 hourε. The mixture was concentrated by rotary evaporation and the residue was stirred into water. The residue waε isolated by filtration and washed with water. Drying gave 4' -amino-5' -chloro-2' ,3' -ethylenedioxyacetophenone (95 mg, 0.41 mmol), m.p. 133-136°C. EXAMPLE 7 1- (4-Amino-5-chloro-2-methoxyphenyl) - 3- (pipβridin-4-yl)propan-1-one The following is the preparation of a compound of Formula I in which R 1 iε chloro, R 3 iε methoxy, R 4 iε a group of Formula (b) in which p iε 0, q iε 2, and R 7 iε hydrogen. Step (a) 4-Amino-5-chloro-2-methoxyacetophenone (12.75 g, 64 mmol), prepared aε in Example 5, waε suspended in THF (125 mL) . The suεpenεion waε added to a -50°C solution of lithium diisopropylamide (16.1 g, 150 mmol) in THF (200 mL) and the mixture was stirred at 0°C for 15 minutes. Pyridine-4- carboxaldehyde (8.0 g, 75 mmol) waε added and the mixture waε allowed to warm to 5°C. Aqueouε ammonium chloride was added and the mixture waε extracted three times with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and concentrated in vacuo to leave a semi-solid residue. Ethyl acetate-hexane waε added and filtration gave 1- (4-amino-5-chloro-2-methoxyphenyl) -3-hydroxy-3- (pyridin-4-yl)propan- 1-one (12.1 g, 40 mmol), m.p. 181-183°C. Step (b) 1- (4-Amino-5-chloro-2-methoxyphenyl) -3-hydroxy-3- (pyridin-4-yl) - propan-1-one (8.6 g, 28 mmol), prepared aε in Example 6, Step (a), waε dissolved in concentrated sulfuric acid (40 mL) and the solution waε stirred at room temperature for 15 minutes. The solution was poured onto ice, basified with ammonium hydroxide, and then filtered to collect a yellow solid. Drying gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 3- (pyridin-4-yl) -2-propen-l-one (7.6 g, 26 mmol), 209-211°C. Step (c) 1- (4-Amino-5-chloro-2-methoxyphenyl) -3- (pyridin-4-yl) -2-propen-l-one (0.5 g, 1.7 mmol), prepared as in Example 6, Step (b) , was dissolved in acetic acid (25 mL) and the solution was hydrogenated over 5% rhodium-alumina catalyst (0.2 g) at 50 psi for 24 hours. The solution was filtered, diluted with water, basified with ammonium hydroxide, and extracted three times with methylene chloride. The combined extractε were dried over εodium sulfate. Evaporation gave 1- (4-amino-5-chloro-2- methoxyphenyl) -3- (piperidin-4-yl)propan-l-one (0.35 g, 1.2 mmol). EXAMPLE 8 1- (4-Amino-5-chloro-2-methoxyphenyl) - 3- (piperidin-4-yl) -2-propβn-l-onβ The following is an alternative method to Example 7, Stepε (a) - (b) Potaεεium hydroxide (5.0 g, 89.3 mmol) waε dissolved in water (25.0 mL) . Ethanol (100 mL) was added to the solution and the mixture was εtirred. 4-Amino-5-chloro-2-methoxyacetophenone (10.0 g, 50.5 mmol), prepared as in Example 5, was added to the stirring εolution and after 5 minuteε pyridine- 4-carboxaldehyde (6.4 g, 60.0 mmol) waε added and the mixture waε εtirred for approximately 12 hourε. The mixture was then diluted with water and filtered to collect a yellow solid. Drying gave 1- (4-amino-5-chloro- 2-methoxyphenyl) -3- (pyridin-4-yl) -2-propen-l-one (12.85 g, 44.5 mmol) . Proceeding as in Example 8, but replacing 4-amino-5-chloro-2-methoxyacetophenone with 4-amino-5-chloro-2,3-ethylenedioxy-acetophenone gave 1- (4-amino-5-chloro- 2,3-ethylenedioxyphenyl) -3- (pyridin-4-yl)propen-l-one, m.p. 209-211°C. Proceeding aε in Example 8, but replacing 4-amino-5-chloro-2-methoxyacetophenone with 4-amino-5-chloro-2,3-dimethoxy- acetophenone gave 1- (4-amino-5-chloro-2,3-dimethoxyphenyl) -3- (pyridin-4- yl) -propen-1-one, m.p. 220-223°C. EXAMPLE 9 1- (4-Amino-5-chloro-2,3-βthylenedioxyphenyl) - 3- (piperidin-4-yl) -2-propan-1-one The following is an alternative method to Example 7, Step (c) . Step (a) A solution of 1- (4-amino-5-chloro-2,3-ethylenedioxyphenyl) - 3- (pyridin-4-yl) -2-propen-l-one (1.55 g, 5 mmol) in 50 mL of THF was hydrogenated over 5% palladium on carbon (0.5 g) for approximately 2 hourε. The mixture waε filtered and concentrated by rotary evaporation. Purification of the residue by silica gel chromatography (2% CH 3 0H-CH 2 C1 2 + 0.1% NH 4 0H) gave 1- (4-amino-5-chloro-2,3-ethylenedioxyphenyl) - 3- (pyridin-4-yl)propan-l-one (1.23 g, 3.8 mmol) . Step (b) A solution of 1- (4-amino-5-chloro-2,3-ethylenedioxyphenyl) - 3- (pyridin-4-yl)propan-1-one (1.23 g, 3.8 mmol) in 15 mL of glacial acetic acid was hydrogenated over 5% rhodium-alumina catalyεt (1.0 g) at 50 pεi for approximately 20 hourε. The mixture waε filtered and the filter was washed several times with ethanol. The combined filtrates were concentrated in vacuo. Purification of the residue by silica gel chromatography (20% CH 3 OH-CH 2 Cl 2 + 0.2% NH 4 OH) gave 1- (4-amino-5-chloro-2,3- ethylenedioxyphenyl) -3- (piperidin-4-yl) -propan-1-one (0.22 g, 0.68 mmol) . EXAMPLE 10 1- ( -Amino-5-chloro-2-methoxyphenyl) - 3- [1- (prop-l-yl)piperidin-4-yl]propan-l-one The following is the preparation of a compound of Formula I in which R 1 iε chloro, R 3 iε methoxy, and R 4 iε a group of Formula (b) , in which p iε 0, q iε 2 and R 7 iε prop-1-yl. 1- (4-Amino-5-chloro-2-methoxyphenyl) -3- (piperidin-4-yl)propan-l-one (0.2 g, 0.67 mmol), prepared aε in Example 3 or Example 7, triethylamine (0.2 ml) , and l-bromopropane (0.065 mL, 0.75 mmol) were diεεolved in DMF (4 mL) and the εolution was εtirred at room temperature for 12 hourε. The εolution waε partitioned between aqueouε ammonium hydroxide and ethyl acetate. The ethyl acetate layer was separated, waεhed with water and then brine, dried over sodium sulfate, and evaporated. Purification of the reεidue by εilica gel chromatography (10% CH 3 0H-CH 2 C1 2 ) gave 1- (4-amino- 5-chloro-2-methoxyphenyl) -3- [1- (prop-l-yl)piperidin-4-yl]propan-l-one which waε then diεεolved in ethanolic hydrochloric acid. Crystallization with ether gave 1- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (prop-1- yl)piperidin-4-yl]propan-l-one hydrochloride (0.15 g, 0.4 mmol), m.p. 200- 201°C. Proceeding as in Example 10, but replacing l-bromopropane with iodomethane, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 3- (l-methylpiperidin-4-yl)propan-l-one hydrochloride, m.p. 179-180°C. Proceeding as in Example 10, but replacing l-bromopropane with iodoethane, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 3- (l-ethylpiperidin-4-yl)propan-l-one hydrochloride, m.p. 128-130°C. Proceeding as in Example 10, but replacing l-bromopropane with iodobutane, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 3- [1- (but-l-yl)piperidin-4-yl] -propan-1-one hydrochloride, m.p. 195-196°C. Proceeding as in Example 10, but replacing l-bromopropane with 1- bromo-2-methylpropane, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (2- methyl-prop-l-yl)piperidin-4-yl]propan-l-one hydrochloride, m.p. 198-199°C. Proceeding aε in Example 10, but replacing l-bromopropane with 1- bromo-3-methylbutane, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (3- methyl-but-l-yl)piperidin-4-yl]propan-l-one hydrochloride, m.p. 178-179°C. Proceeding aε in Example 10, but replacing l-bromopropane with 1-bromopentane, gave l- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (pent-1-yl) - piperidin-4-yl]propan-l-one hydrochloride, m.p. 196-197°C. Proceeding aε in Example 10, but replacing l-bromopropane with 1-bromohexane, gave 1- (4-amino-5-chloro- -methoxyphenyl) -3- [1- (hex-l-yl) - piperidin-4-yl]propan-1-one hydrochloride, m.p. 212-213°C. Proceeding aε in Example 10, but replacing l-bromopropane with 3-bromopropene, gave 1- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (2- propenyl) -piperidin-4-yl]propan-l-one hydrochloride, m.p. 162-163°C. Proceeding aε in Example 10, but replacing l-bromopropane with 1-chloro-2-methoxyethane, gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 3- [1- (2-methoxy-ethyl)piperidin-4-yl]propan-l-one hydrochloride. Proceeding aε in Example 10, but replacing l-bromopropane with 2- bromo-1- [ (dimethylaminoεulfonyl)amino]ethyl, gave 1- (4-amino-5-chloro- 2-methoxy-phenyl) - 3-(l- [2- (dimethylaminoεulfonyl)aminoethyl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 195-196°C. Proceeding aε in Example 10, but replacing l-bromopropane with 2- bromo-1- [ (dimethylaminocarbonyl)amino]ethyl, gave 1- (4-amino-5-chloro- 2-methoxy-phenyl) - 3-{l- [2- (dimethylaminocarbonyl)aminoethyl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 167-171°C. Proceeding aε in Example 10, but replacing l-bromopropane with 2- bromo-1- [(methoxycarbonyl)amino]ethyl, gave 1- (4-amino-5-chloro- 2-methoxyphenyl) -3-{l- [2- (methoxycarbonyl)aminoethyl]piperidin-4-yl}propan- 1-one hydrochloride, m.p. 239-240°C. Proceeding aε in Example 10, but replacing l-bromopropane with 2- bromo-1- [(trifluoromethylεulfonyl)amino]ethyl, gave 1- (4-amino-5-chloro- 2-methoxy-phenyl) - 3-{l- [2- (trifluoromethylεulfonyl)aminoethyl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 235-238°C. Proceeding aε in Example 10, but replacing l-bromopropane with 3- bromo-1- [ (methylεulfonyl)amino]propyl, gave 1- (4-amino-5-chloro- 2-methoxyphenyl) -3-{l- [3- (methylεulfonyl)aminoprop-1- yl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 194-195°C. Proceeding aε in Example 10, but replacing l-bromopropane with iodobutane and 1- (4-amino-5-chloro-2-methoxyphenyl) -3- (piperidin-4- yl)propan-1-one with 1- (4-amino-5-chloro-2,3-ethylenedioxyphenyl) - 3- (piperidin-4-yl)propan-l-one, gave 1- (4-amino-5-chloro- 2,3-ethylenedioxyphenyl) -3- [1- (but-l-yl) -piperidin-4-yl]propan-1-one hydrochloride, m.p. 265-267°C. Proceeding as in Example 10, but replacing l-bromopropane with iodobutane and 1- (4-amino-5-chloro-2-methoxyphenyl) -3- (piperidin-4- yl)propan-1-one with 1- (4-amino-5-chloro-2,3-dimethoxyphenyl) -3- (piperidin- 4-yl)propan-1-one, gave 1- (4-amino-5-chloro-2,3-dimethoxyphenyl) - 3- [1- (but-l-yl)piperidin-4-yl] -propan-1-one hydrochloride, m.p. 175-176°C. EXAMPLE 11 1- (4-A__ino-5-chloro-2-__ethoxyphenyl) - 3 - {l- [2- (methylsulfonyl) a_ninoethyl] piperidin-4-yl}propan-l-one The following is the preparation of a compound of Formula I in which R 1 iε chloro, R 3 iε methoxy, and R 4 iε a group of Formula (b) in which p iε 0, q is 2 and R 7 is 2- [ (methylεulfonyl)amino]ethyl. Ethylenimine (40 mg, 0.9 mmol) waε diεεolved in toluene (5 mL) and the εolution waε cooled in an ice bath. A εolution of methaneεulfonyl chloride in toluene (1 mL, 0.1 mg, l mmol) waε εlowly added and the mixture waε εtirred for 20 minuteε to form a εolution of 1- [2- (methylεulphonyl)ethyl]ethylenimine. 1- (4-Amino-5-chloro-2-methoxyphenyl) -3- (piperidin-4-yl)propan-l-one (240 mg, 0.8 mmol), prepared aε in Example 3 or Example 7, was diεεolved in THF (20 mL) and the εolution of 1- [2- (methylεulphonyl)ethyl]ethylenimine waε added through a filter. The mixture waε heated under reflux for 1 hour and then concentrated in vacuo. The reεidue was disεolved in ethyl acetate and thiε solution was then washed three times with water, dried over εodium sulfate, and evaporation. Purification by silica gel chromatography (15% CH j OH-CH j C^) gave 1- (4-amino-5-chloro-2-methoxyphenyl) -3-{l- [2- (methylεulfonyl)aminoethyl] -piperidin-4-yl}propan-l-one. Crystallization from ethanolic hydrochloric acid gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 3-{l- [2- (methylsulfonyl)aminoethyl] -piperidin-4-yl}propan-l-one hydrochloride, m.p. 123-126°C. EXAMPLE 12 1- [4-Amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 3-{l- [2- (methylsulfonyl)-_minoethyl]piperidin-4-yl}propan-l-one The following is the preparation of a compound of Formula I in which R 1 is chloro, R 3 is 3,5-dimethoxybenzyloxy and R 4 is a group of Formula (b) , in which p is 0, q is 2 and R 7 is 2- (methylsulfonyl)aminoethyl. Step (a) 1- [4-Amino-5-chloro-2-methoxyphenyl] -3-{l- [2- (methylsulfonyl)aminoethyl] -piperidin-4-yl}propan-l-one (1.19 g, 2.8 mmol), prepared as in Example 11, was dissolved in dichloroethane (50 mL) . Boron tribromide in methylene chloride (4 mL, 1.0 g, 4.0 mmol) was added and the mixture was stirred for approximately 12 hours. The mixture waε then poured over ice and methylene chloride (150 mL) and ammonium hydroxide) were added. Thiε bilayer mixture was stirred until a solution had formed in the methylene chloride layer. The aqueous layer was removed and combined with fresh methylene chloride (100 mL) and this bilayer mixture was stirred. The methylene chloride layers were combined and dried over potasεium carbonate. Filtration and concentration gave 1- (4-amino-5- chloro-2-hydroxyphenyl) -3-{l- [2- (methylsulfonyl)__minoethyl]piperidin-4-yl}propan-l-one (0.8 g, 2.0 mmol). Step (b) 1- (4-Amino-5-chloro-2-hydroxyphenyl) -3-{l- [2- (methylsulfonyl)aminoethyl] -piperidin-4-yl}propan-l-one (0.78 g, 1.93 mmol), 3,5-dimethoxybenzyl chloride (0.396 g, 2.12 mmol), and potassium carbonate (2.6 g, 18.8 mmol) were combined in DMF (« 2 mL) and the mixture waε εtirred at ambient temperature for 48 hours. Additional 3,5-dimethoxybenzyl chloride (0.05 g, 0.13 mmol) was added and the mixture waε stirred for 24 hourε. The εolvent was removed under reduced pressure and methylene chloride and aqueous sodium bicarbonate were added to the remaining solids and thiε bilayer mixture was εtirred. The methylene chloride layer was separated, washed twice with water, and dried over potaεεium carbonate. Filtration and concentration gave a crude product (1.2 g) . Purification by εilica gel chromatography (3% CH 3 0H-CH 2 C1 2 ) gave 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] -3-{l- [2- (methylεulfonyl)aminoethyl] -piperidin-4-yl}propan-l-one (0.53 g, 0.98 mmol) . Cryεtallization from ethanolic hydrochloric acid gave 1- [4-amino-5- chloro-2- (3,5-dimethoxybenzyloxy)phenyl] -3-{l- [2- (methylεulfonyl)aminoethyl] -piperidin-4-yl}propan-l-one hydrochloride (0.54 g, 0.93 mmol), m.p. 123-126°C. Proceeding aε in Example 12, Step (a) , but replacing l- [4-amino-5- chloro-2-methoxy-phenyl] -3-{l- [2- (methylεulfonyl)aminoethyl]piperidin-4-yl}propan-l-one with 1- (4-amino- 5-chloro-2-methoxyphenyl) -3- [1- (but-1-yl)piperidin-4-yl] -propan-l-one, and then correεpondingly aε in Example 12, Step (b) , gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -3- [1- (but-l-yl) - piperidin-4-yl]propan-l-one hydrochloride, m.p. 179-182°C. Proceeding aε in Example 12, Step (a), but replacing l- [4-amino-5- chloro-2-methoxyphenyl] -3-{l- [2- (methylεulfonyl)aminoethyl]piperidin-4-yl}propan-l-one with 1- (4-amino- 5-chloro-2-methoxyphenyl) -3- [1- (pent-l-yl)piperidin-4-yl] -propan-1-one, and then correεpondingly aε in Example 12, Step (b) , gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -3- [1- (pent-1-yl) - piperidin-4-yl]propan-1-one hydrochloride, m.p. 174-176 β C. Proceeding aε in Example 12, but replacing 1- [4-amino-5-chloro-2- methoxy-phenyl] -3-{l- [2- (methylsulfonyl)aminoethyl]piperidin-4-yl}propan-l- one with 1- (4-amino-5-chloro- -methoxyphenyl) -3- [1- (2- methoxyethyl)piperidin-4-yl] -propan-1-one, and then correspondingly as in Example 12, Step (b) , gave 1- [4-amino-5-chloro- 2- (3,5-dimethoxybenzyloxy)phenyl] -3- [1- (2-methoxyethyl) - piperidin-4-yl]propan-l-one hydrochloride, m.p. 183-184°C. Proceeding as in Example 12, Step (a), but replacing 1- [4-amino-5- chloro-2-methoxyphenyl] -3-{l- [2- (methylsulfonyl)c_minoethyl]piperidin-4-yl}propan-l-one with 1- [4-amino-5- chloro-2-methoxyphenyl] -3-{l- [2- (dimethylaminosulfonyl)amino- ethyl]piperidin-4-yl}propan-l-one, and then correspondingly aε in Example 12, Step (b) , gave 1- [4-amino-5-chloro-2- (3,5-dimethoxybenzyloxy)phenyl] - 3-{l- [2- (dimethylaminoεulfonyl)aminoethyl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 173-176°C. Proceeding aε in Example 12, Step (b) , but replacing 3,5-dimethoxybenzyl chloride with benzyl chloride, gave 1- (4-amino-5- chloro-2-benzyloxyphenyl) - 3-{l- [2- (methylεulfonyl)aminoethyl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 193-194°C. Proceeding as in Example 12, Step (b) but replacing 3,5-dimethoxybenzyl chloride with 3-methoxybenzyl chloride, gave 1- [4- amino-5-chloro-2- (3-methoxy-benzyloxy)phenyl] - 3-{l- [2- (methylεulfonyl)aminoethyl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 174-176°C. Proceeding as in Example 12, Step (a), but replacing 1- (4-amino-5- chloro-2-methoxyphenyl) -3-{l- [2- (methylεulfonyl)aminoethyl]piperidin-4-yl}propan-l-one with 1- [4-amino-5-chloro-2-methoxyphenyl] -5- (piperidin-1-yl)pentan-l-one, and then aε in Example 12, Step (b) , but replacing 3,5-dimethoxybenzyl chloride with iodoethane, gave 1- [4-amino-5-chloro-2-ethoxyphenyl] - 5- (piperidin-1-yl) -pentan-l-one hydrochloride, m.p. 230-231°C. Proceeding aε in Example 12, Step (a), but replacing 1- (4-amino-5- chloro-2-methoxyphenyl) -3-{l- [2- (methylsulfonyl)aminoethyl]piperidin-4-yl}propan-l-one with 1- [4-amino-5-chloro-2-methoxyphenyl] -5- (piperidin-1-yl)pentan-l-one, and then as in Example 12, Step (b) , but replacing 3,5-dimethoxybenzyl chloride with l-bromopropane, gave 1- [4-amino-5-chloro-2- (prop-1-yloxy)phenyl] - 5- (piperidin-1-yl)pentan-1-one hydrochloride, m.p. 232-233°C. Proceeding as in Example 12, Step (a), but replacing 1- (4-amino-5- chloro-2-methoxyphenyl)-3-{l-[2- (methylsulfonyl)aminoethyl]piperidin-4-yl}propan-l-one with 1- [4-amino-5-chloro-2-methoxyphenyl] -5- (piperidin-1-yl)pentan-l-one, and then as in Example 12, Step (b) , but replacing 3,5-dimethoxybenzyl chloride with 3,5-dimethylbenzyl chloride, gave 1- [4-amino-5-chloro- 2- (3,5-dimethylbenzyloxy) -phenyl] -5- (piperidin-l-yl)pentan-l-one hydrochloride, m.p. 218-233°C. Proceeding as in Example 12, Step (a), but replacing 1- [4-amino-5- chloro-2-methoxyphenyl] -3-{l- [2- (methylεulfonyl)__minoethyl]piperidin-4-yl}propan-l-one with l- (4-amino- 5-chloro-2-methoxyphenyl) -5- (4-aminocarbonylpiperidin-l-yl) -pentan-l-one, and then aε in Example 12, Step (b) , but replacing 3,5-dimethoxybenzyl chloride with 3-methoxybenzyl chloride, gave 1- [4-amino-5-chloro- 2- (5-methoxybenzyloxy)phenyl] -5- (4-aminocarbonylpiperidin-l-yl) - pentan-l-one hydrochloride, m.p. 204-205°C. EXAMPLE 13 1- (4-Amino-5-chloro-2-methoxyphenyl) - 3-{l- [3- (4-methoxyphenyl)prop-l-yl]piperidin-4-yl}propan-l-one The following is the preparation of a compound of Formula I in which R 1 iε chloro, R 2 iε hydrogen and R 3 iε methoxy and R 4 is a group of Formula (b) , in which p is 0, q is 2 and R 7 is 3- (4-methoxyphenyl)prop-1- yi- Step (a) A mixture of 1- (4-amino-5-chloro-2-methoxyphenyl) -3-pyridin-4-yl- propan-1-one (1.5 g, 5.16 mmol), prepared aε in Example 3 or 7, 3- (4-methoxyphenyl) -1-iodopropane (1.64 g, 5.93 mmol) in 13 mL of acetonitrile was heated under nitrogen at reflux for approximately 4 hours. The mixture was concentrated in vacuo and purification of the residue by silica gel chromatography (5% O^OH-CHzC , + 0.1% NH 4 OH) gave 1- (4-amino-5- chloro-2-methoxyphenyl) -3-{l- [3- (4-methoxyphenyl)prop-1-yl] - pyridinyl-4-yl}propan-l-one hydroiodide (1.82 g, 3.28 mmol). Step (b) A solution of(4-amino-5-chloro-2-methoxyphenyl) - 3-{l- [3- (4-methoxyphenyl) -prop-l-yl]pyridinyl-4-yl}propan-l-one hydroiodide (1.82 mg, 3.28 mmol) in 30 mL of DMF was hydrogenated over a platinum(IV) oxide catalyst (350 mg) at 50 psi. The reaction mixture was filtered and concentrated under high vacuum. The residue was dissolved in 150 mL of methylene chloride and the solution was diluted with a solution of ammonium hydroxide. The methylene chloride layer was separated and washed with ice water (3x) . The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo. Crystallization of the residue from ethanolic hydrochloric acid gave 1- (4-amino-5-chloro-2-methoxy-phenyl) -3-{l- [3- (4- methoxyphenyl)prop-l-yl]piperidin-4-yl}propan-l-one hydrochloride (1.33 g, 3.09 mmol), m.p. 188-190°C. Proceeding as in Example 13, Step (a), but replacing 3- (4- methoxyphenyl) -1-iodopropane with 3- (3,5-dimethoxyphenyl) -1-iodopropane, and then correspondingly as in Example 13, Step (b) , gave 1- (4-amino-5- chloro-2-methoxy-phenyl) -3-{l- [3- (3,5-dimethoxyphenyl)prop-1- yl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 160-163°C. Proceeding aε in Example 13, Step (a), but replacing 3- (4- methoxyphenyl) -1-iodopropane with 3- (3,4-dimethoxyphenyl) -1-iodopropane, and then correεpondingly aε in Example 13, Step (b) , gave 1- (4-amino-5- chloro-2-methoxy-phenyl) -3-{l- [3- (3,4-dimethoxyphenyl)prop-1- yl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 177-179°C. Proceeding as in Example 13, Step (a), but replacing 3- (4- methoxyphenyl) -1-iodopropane with 3- (3,4-ethylenedioxyphenyl) - 1-iodopropane, and then correspondingly as in Example 13, Step (b) , gave 1- (4-amino-5-chloro-2-methoxy-phenyl) -3-{l- [3- (3,4-ethylenedioxyphenyl)prop- l-yl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 168-170°C. Proceeding as in Example 13, Step (a), but replacing 3- (4- methoxyphenyl) -1-iodopropane with 3- (3,4-methylenedioxyphenyl) - 1-iodopropane, and then correspondingly aε in Example 13, Step (b) , gave 1- (4-amino-5-chloro-2-methoxy-phenyl) -3-{l- [3- (3,4-methylenedioxyphenyl)prop- l-yl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 200-202°C. Proceeding as in Example 13, Step (a), but replacing 3- (4- methoxyphenyl) -1-iodopropane with 3- (3,4,5-trimethoxyphenyl) -1-iodopropane, and then correspondingly as in Example 13, Step (b) , gave 1- (4-amino-5- chloro-2-methoxy-phenyl) -3-{l- [3- (3,4,5-trimethoxyphenyl) rop-1- yl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 180-182°C. Proceeding aε in Example 13, Step (a), but replacing 1- (4-amino-5- chloro-2-methoxyphenyl) -3-pyridin-4-ylpropan-l-one with 1- (4-amino-5- chloro-2,3-ethylenedioxyphenyl) -3-pyridin-4-ylpropan-l-one, and then correspondingly as in Example 13, Step (b) , gave 1- (4-amino-5-chloro-2,3- ethylenedioxyphenyl) -3-{l- [3- (4-methoxyphenyl)prop-l- yl]piperidin-4-yl}propan-l-one hydrochloride, m.p. 188-189°C. EXAMPLE 14 1- (4-Amino-5-chloro-2-___thoxyphenyl) - 5- iperidin-l- lpentan-1-one The following is the preparation of a compound of Formula I in which R 1 is chloro, R 2 is hydrogen, R 3 is methoxy and R 4 is a group of Formula (a) , in which p is 0, n is 4 and R 3 and R 6 together are piperdin-1-yl. Step (a) Magnesium (236 g, 9.71 mol) was suspended in 3.5 L of THF under nitrogen and l-bromo-4-chlorobutane (1.11 L, 8.68 M, 9.63 mol) waε added at a rate εuch that the temperature of the mixture remained below 25°C. A solution of _\t-methoxy-2v ' -methyl -4 -amino- 5 - chloro- 2 -methoxybenzamide (400 g, 1.64 mol), prepared as in Example 2, under nitrogen in 4 L of THF waε cooled to -20°C and 410 mL of chlorotrimethylεilane waε added. The mixture waε allowed to warm to between -12 and 30°C and then 2.5 L of the solution containing the magnesium and l-brσmo-2-chlorobutane was added over approximately 20 minuteε. The mixture was cooled to 5°C and then diluted with 420 mL of concentrated hydrochloric acid in 5 L of water. The mixture waε heated to 32°C, εtirred for 15 minutes and then diluted with approximately 2 L of ethyl acetate. The organic layer waε εeparated and washed sequentially with 2 L of water and 2 L of 1:1 water/saturated εodium chloride εolution and saturated sodium chloride solution. All aqueous layerε were combined and extracted with ethyl acetate. All organic layers were combined, dried over εodium εulfate, filtered and concentrated. The reεidue waε combined with hot hexane and allowed to stand at room temperature for approximately 12 hourε giving a precipitate. The precipitate waε iεolated by filtration and washed with hexane. Drying in a vacuum oven at between 50 and 55°C under a nitrogen gas bleed gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5-chloropentan-l-one (365 g, 1.33 mol) . Step (b) A mixture of 1- (4-amino-5-chloro-2-methoxyphenyl) - 5-chloropentan-1-one (365 g, 1.33 mol), piperidine (620 g, 7 mol) and sodium iodide (30 g, 0.2 mol) in 1 L of DMF was heated at between 78 and 82°C for 4 hours. The reaction mixture was allowed to cool to 50°C, then stirred for approximately 12 hours and 5 L of water waε added. The mixture waε stirred at 25 to 30°C for 1 hour giving a precipitate and the precipitate was isolated by filtration. The precipitate was washed with 4 L of water and dried under suction for 1 hour. The precipitate was dissolved in approximately 2 L of ethyl acetate by heating to approximately 50°C and then 130 mL of a solution of concentrated hydrochloric acid in a total of 4 L of water was added. The mixture was stirred for 30 minutes and then stirred for 3 hours in and ice- water bath giving a precipitate. The precipitate was isolated by filtration and washed with 1 L of cold 1:1 water/ethyl acetate and then 1 L of ethyl acetate. The precipitate was dried in a vacuum oven at between 45 and 50°C under a nitrogen gas bleed for 24 hours, at 50 to 55°C for 24 hours and then at room temperature for 48 hours. The dry precipitate was dissolved in approximately 9 L of boiling methanol. The solution was filtered and then distilled under vacuum to a volume of approximately 4 L. Reagent alcohol was added and the mixture waε diεtilled under atmospheric pressure to a boiling point of between 72 and 74°C and a total volume of approximately 5 L. The remaining mixture was stirred at room temperature for approximately 12 hours and then in an ice bath for 4 hours giving a precipitate. The precipitate waε iεolated by filtration and waεhed with approximately 1.5 L of alcohol. The iεolated precipitate waε dried by suction for 2 hourε and then in a vacuum oven at between 55 and 60°C under a nitrogen gaε bleed for approximately 12 hourε and the dry precipitate was passed through a size 10 clinical εcreen. Further drying in a vacuum oven at between 55 and 60°C under a nitrogen gaε bleed for 48 hourε gave 1- (4-amino-5-chloro-2-methoxyphenyl) -5-piperidin-1- ylpentan-1-one hydrochloride (357 g, 0.99 mol), m.p. 220-222°C. Proceeding aε in Example 14 but replacing piperidine with 4-methyl- piperidine gave 1- (4-amino-5-chloro- -methoxyphenyl) -5- (4-methylpiperidin- 1-yl-pentan-l-one hydrochloride, m.p. 197-198°C. EXAMPLE 15 1- (4-Amino-5-chloro-2-methoxyphenyl) - 5-piperidin-1-ylpentan-1-one The following iε the preparation of a compound of Formula I in which R 1 iε chloro, R 2 iε hydrogen, R 3 iε methoxy and R 4 iε a group of Formula (a) , in which p is 0, n is 4 and R 3 and R 6 together are piperdin-1-yl. A suspension of 5- (piperdin-1-yl)valeric acid hydrochloride (6.6 g, 30 mmol) in 100 mL of THF was cooled in an ice bath and 100 mL of IN lithium bis (trimethylsilyl)amide in THF was added. The ice bath was removed and the resulting solution was stirred at room temperature for 1 hour. A mixture of methyl 2-methoxy-4-amino-5-chlorobenzoate (2.15 g, 10 mmol) and chlorotrimethylεilane (2.5 mL, 20 mmol) in 25 mL of THF was cooled in an ice bath and 20 mL of 12. lithium bis(trimethylsilyl)amide in THF was added. The solution containing the 5-piperdin-1-ylvaleric acid and IN lithium bis(trimethylsilyl)amide was cooled in an ice bath and the mixture containing the methyl 2-methoxy-4-amino-5-chlorobenzoate was added over 5 minutes. The reaction mixture was removed from the ice bath and stirred at 50 to 55°C for 2 hours and then a solution of 25 mL of concentrated hydrochloric acid in 175 mL of water was added. The mixture was stirred at 50 to 55°C under a gentle stream of nitrogen and then 120 mL of ethyl acetate was added. The mixture was stirred in an ice bath for 1 hour giving a precipitate. The precipitate was isolated by filtration and washed with ethyl acetate. The precipitate was stirred in approximately 40 mL of boiling isopropanol for 30 minutes and then for 1 hour in an ice bath. The precipitate was isolated by filtration and washed with isopropanol. Drying in a vacuum oven at between 55 and 60°C under a nitrogen gas bleed for 18 hours gave 1- (4-amino-5-chloro-2-methoxyphenyl) - 5-piperidin-l-ylpentan-l-one hydrochloride (2.9 g, 8 mmol) . EXAMPLE 16 The following are representative pharmaceutical formulations containing a compound of Formula I. ORAL FORMULATION A representative εolution for oral adminiεtration contains: Compound of Formula I 100-1000 mg Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.ε. to 100 mL INTRAVENOUS FORMULATION A representative solution for intravenouε adminiεtration containε: Compound of Formula I 10-100 mg Dextroεe Monohydrate q.ε to make iεotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL TABLET FORMULATION A representative tablet form of a compound of Formula I may contain: Compound of Formula I 1 % Microcrystalline cellulose 73 % Stearic Acid 25 % Colloidal Silica 1 % EXAMPLE 17 THORACIC ESOPHAGUS 5-HT 4 RECEPTOR ASSAY The following deεcribeε an in vitro aεεay which utilizes rat isolated esophageal muscularis mucosae to identify test compounds which are 5-HT 4 receptor ligands. Thoracic eεophagi are iεolated from male, Sprague-Dawley ratε and placed in Tyrode'ε εolution. The outer εtriated muεcle iε removed to reveal the muεculariε mucosae. Each mucosae iε εuεpended vertically in a 10 mL tissue bath containing methysergide (1 μM) , cocaine (30 μM) , and corticosterone (30 μM) in Tyrode' s solution maintained at 37°C and constantly aerated with a 95% 0 2 and 5% C0 2 gas mixture. A resting tenεion of 1 g is applied to each tisεue and thereafter 0.5 g iε reapplied at 15 minute intervals. A steady state contraction to carbachol (3 μM) iε produced and then the tiεεue iε expoεed to 5-HT in a cumulative-concentration faεhion, increaεing in concentration until maximal or near maximal relaxation iε achieved. The 5-HT produces a concentration-dependent, 5-HT 4 receptor mediated relaxation of the muscularis mucosae tisεue. The tiεεue iε expoεed to drug free Tyrode'ε solution for 30 minutes and then again contracted with carbachol. The tiεsue is then expoεed to teεt compound. If the teεt compound doeε not itself elicit relaxation of the eεophageal muεculariε mucosae, the tissue is expoεed to 5-HT in the preεence of the teεt compound. Compoundε which intrinsically produce relaxation are characterized as 5-HT 4 receptor agonists. Compounds which inhibit the relaxation reεponses to 5-HT are characterized aε 5-HT 4 receptor antagoniεts. Proceeding as in Example 17, the following results were obtained for the compounds of this invention: Compound Affinity Conεtant (-log) A 7.4 B 7.5 C 8.4 D 8.2 E 8.8 F 10.6 A: 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (piperidinyl-1- yl)pentan-l-one hydrochloride B: 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (4-methylpiperidinyl-l- yl)pentan-l-one hydrochloride C: 1- (4-amino-5-chloro-2-methoxy-phenyl) -3-{2- [(methylsulfonyl)amino]ethyl}piperdin-4-yl]propan-1-one hydrochloride D: 1- (4-amino-5-chloro-2-methoxy-phenyl) -3- [1- (n-butyl)piperdin-4- yl]propan-1-one hydrochloride E: 1- (4-amino-5-chloro-2-methoxy-phenyl) -3-{l- [3- (3,4-dimethoxyphenyl)prop-1-yl]piperdin-4-yl}propan-l-one hydrochloride F: 3- (4-methoxyphenyl)prop-1-yl, namely 1- (4-amino-5-chloro-2,3- ethylenedioxyphenyl) -3-{l- [3- (4-methoxyphenyl) - prop-l-yl]piperdin-4-yl}propan-l-one hydrochloride EXAMPLE 18 PROKINETIC ASSAY The following describes an in vivo method of determining prokinetic activity by measuring the extent the drug affects the rate of gastric emptying of test meal in rats. The method is that described by Droppleman et al. , previously cited. Teεt meal is prepared by slowly adding 20 g of cellulose gum (Herculeε Inc., Wilmington, Delaware) to 200 mL of cold diεtilled water that iε being mixed in a Waring blender at approximately 20,000 rpm. Mixing continueε until complete diεperεion and hydration of the cellulose gum takeε place (approximately 5 min) . Three beef bouillon cubes are diεεolved in 100 mL of warm water and then blended into the celluloεe εolution followed by 16 g of purified caεein (Sigma Chemical Co., St. Louiε, MO) , 8 g of powdered confectionerε sugar, 8 g of comstarch, and 1 g of powdered charcoal. Each ingredient is added slowly and mixed thoroughly resulting in approximately 325 mL of a dark gray to black, homogenous paste. The meal is then refrigerated overnight during which time trapped air escapes. Prior to the assay the meal is removed from the refrigerator and allowed to warm to room temperature. Mature (170 to 204 g) male Sprague-Dawley rats are deprived of food for 24 hours with water ad libitum. On the morning of the study each animal is weighed and randomly aεεigned to treatment groupε conεiεting of ten animals per group. Each rat receives either vehicle, test compound or the reference standard metoclopramide by intraperitoneal injection. At 0.5 hours post injection 3.0 mL of test meal is orally administered to each rat with a 5.0 mL disposable syringe. Five test meal samples are weighed on an analytical balance and these weightε are averaged to find a mean teεt meal weight. At 1.5 hours post injection each rat is sacrificed by carbon dioxide asphyxiation and the stomach is removed by opening the abdomen and carefully clamping and cutting the esophagus just below the pyloric εphincter. Taking care not to lose any of the its contents, each stomach is placed on a small, pre-weighed and correspondingly labeled 7 mL weigh boat and immediately weighed on an analytical balance. Each stomach is then cut open along the lesser curvature, rinsed with tap water, gently blotted dry to remove exceεε moiεture and weighed. The amount of test meal remaining in the stomach iε repreεented by the difference between the weight of the full εtomach and the weight of the εtomach empty. The difference between the amount of teεt meal remaining and the mean test meal weight representε the quantity of teεt meal that emptieε during the 1.5 hour poεt injection period. Responseε are repreεented aε gramε of meal emptied or percent change from control. Means and standard deviationε of the test groups are compared to those of the reference groupε. Significance iε determined via Dunnett'ε t-teεt (Statiεtical Aεsociation Journal, December 1955, 1096-112) . Proceeding as in Example 18, compounds of this invention were determined to poεεess prokinetic activity. EXAMPLE 19 ANXIOLYTIC BEHAVIOR ASSAY The following describes an in vivo method for determining anxiolytic activity by measuring the extent the drug affects the natural anxiety of mice when exposed to a novel, brightly lighted environment. Naive male C5BI/6J mice, 18-20 g, are kept in groups of 10 mice in quarters controlled for sound, temperature and humidity. Food and water are available ad libitum. The mice are kept on a 12 hour light and 12 hour dark cycle, with lights on at 6:00 a.m. and off at 6:00 p.m. All experiments begin at least 7 dayε after arrival on site. The automated apparatus for detecting changes in exploration is obtained from Omni-Tech Electronics Columbus Ohio and is similar to that of Crawley and Goodwin (1980), as described in Kilfoil et al., cited previously. Briefly, the chamber consists of a plexiglass box (44 x 21 x 21 cm) , divided into two chambers by a black plexiglass partition. The partition dividing the two chambers contains a 13 x 5 cm opening through which the mouse can easily pass. The dark chamber has clear sides and a white floor. A fluorescent tube light (40 watt) placed above the chambers provides the only illumination. The Digiscan Animal Activity Monitor System RXYZCM16 (Omni-Tech Electronics) records the exploratory activity of the mice within the teεt chamberε. Prior to commencement of the εtudy the mice are given 60 min to acclimatize to the laboratory environment. After a mouse receives an intraperitoneal (i.p.) injection of either test compound or vehicle it iε returned to itε home cage for a 15 min poεt-treatment period. The mouse is then placed in the center of the light chamber and monitored for 10 minutes. Anxiolysis is seen aε a general increaεe in exploratory activity in the lighted area. An increaεe in exploratory activity is reflected by increaεed latency (the time for the mouεe to move to the dark chamber when firεt placed in the center of the lighted area) , increaεe in εhuttle activity, increaεed or unaltered locomotor activity (number of grid lineε crossed) and decreased time spent in the dark compartment. EXAMPLE 20 WITHDRAWAL ANXIETY ASSAY The following deεcribeε an in vivo procedure for determining amelioration of the εymptomε cauεed by withdrawal from addictive εubεtanceε by meaεuring the extent the drug affectε the anxiety that occurs in mice after chronically treating with an addictive substance and then abruptly ceasing the treatments. Naive male BKW mice (25-30 g) are caged in groupε of ten in quarters controlled for sound, temperature and humidity. Food and water are available ad libitum. The mice are kept on a 12 hour light cycle and 12 hour dark cycle, with lights on at 6:00 a.m. and off at 6:00 p.m. All experimentε begin at leaεt 7 days after arrival on site. Levels of anxiety are determined by the two-compartment exploratory model of Crawley and Goodwin (see Example 19) . Anxiolysiε iε εeen aε a general increaεe in exploratory activity in the lighted area. An increaεe in exploratory activity is reflected by increased latency (the time for the mouse to move to the dark chamber when first placed in the center of the lighted area) , increased or unaltered locomotor activity (number of grid lines crossed) , increased number of rears and decreased time spent in the dark compartment. Increased exploratory activity in the lighted area is induced by treating the mice for 14 days with ethanol (8.0 % w/v in drinking water), nicotine (0.1 mg/kg, i.p., twice daily) or cocaine (1.0 mg/kg, i.p., twice daily) . Anxiolysis iε assessed 1, 3, 7 and 14 days after commencement of the drug regime. The treatment is abruptly ceased and exploratory activity in the lighted area is determined 8, 24 and 48 hours thereafter. Vehicle or test compoundε are administered during the withdrawal phase by intraperitoneal injection. Responses are represented as inhibition of the decrease in anxiolytic behavior after the ethanol, cocaine or nicotine treatment is ceased. EXAMPLE 21 COGNITIVE ENHANCEMENT ASSAY The following describes a model to determine the cognitive enhancing activity by measuring the extent the teεt compound could alleviate the cognitive deficit induced by atropine (30 mg/kg, i.p.) uεing the Morriε Water Maze. Sprague Dawley rats (240-260 g) were kept in the laboratory the night prior to testing, and remained there throughout the experiment. The Morriε Water Maze consistε of a circular pool made from black plexiglaεε (122 cm diameter, 46 cm in height, with a 15 cm rim) , filled with opaque water to a height of 35 cm. A hidden platform consiεting of black plexiglaεε was placed 1-2 cm below the surface of the water. The pool was divided into four quadrantε, arbitrarily correεponding to north, εouth, eaεt and weεt. The platform waε located in the εouth quadrant, about 24 cm from the εide. Objects of high contrast were placed about the room to serve as spatial cueε. A TV camera tracked the swim path of the rats, and the data thus obtained was examined to determine the time in seconds the rats took to find the platform (escape latency) . Test trials were initiated by placing a rat into one of the four quadrants, facing the wall. Testing consisted of a block of six trials (starting first in the north quadrant, then east, south, west, north, and finally east) on each of two consecutive days. During each trial the rat waε allowed 90 εecondε to find the platform. When the rat successfully found the platform, it was given 30 seconds to "study" the spatial cues. When the rat failed to find the platform within 90 seconds, it was given a score of 90 seconds, and placed on the platform for 30 seconds. The following groups of 8 rats each were used: 1) vehicle-treated controls; 2) atropine treated-controls; 3) atropine plus teεt drug. Thuε the studies were designed to determine whether the test drug could alleviate the cognitive deficit induced by atropine (30 mg/kg, i.p.). Statiεtical tests were applied to test for heterogeneity of the learning curves, and separation of the learning curves. Proceeding as in Example 21, compounds of this invention were determined to posseεε cognition enhancing propertieε. For example, 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (piperidinyl-1-yl)pentan-l-one hydrochloride and 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (4- methylpiperidinyl-1-yl)pentan-1-one hydrochloride were effective after i.p. administration (lOng/Kg - 1 mg/Kg) in this study. EXAMPLE 22 TOXICITY Rats were administered oral doses of 5, 15 and 50 mg/Kg/day of 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (piperidinyl-1-y1)pentan-1-one hydrochloride for one month. No treatment related pathalogical changes were present at any of the doses given. While the present invention has been described with respect to specific embodiments thereof, it will be understood by those εkilled in the art that variouε changeε may be made and equivalentε may be εubεtituted without departing from the true εpirit and εcope of the invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims: WE CLAIM: 1. A compound of Formula I: in which R 1 is halo; R 2 iε hydrogen or C,^)alkyloxy and R 3 iε (C M )alkyloxy or phenyl (C )alkyloxy (wherein the phenyl iε optionally substituted with one to three substituents independently selected from halo, hydroxy, (C )alkyl, (C M )alkyloxy, nitro, amino, aminocarbonyl, (C,.,)alkylamino, di (C )alkylamino, (C M )alkanoylamino and 3,4-methylenedioxy) or R 2 and R 3 together are methylenedioxy or ethylenedioxy; and R 4 is a group of Formula (a) or (b) * in which n is 3, 4 or 5; p is 0 or 1; q iε 1 or 2; R 5 and R 6 are each (C M )alkyl or together form -(CH 2 ) 4 -, - Cl^) 6 - , - (C m) 2 0 (CH 2 ) 2 - or -CHR 8 CH 2 CR 9 R 10 CHR I1 CH 2 - in which R 8 and R u are each hydrogen or together are -(CHj),- in which t iε 1, 2 or 3, R 9 iε hydrogen, hydroxy, (C|.g)alkyl, (C 3 ^)alkenyl or (C,.,)alkyloxy and R 10 iε hydrogen, (C,^)alkyl or (C 3 ^)alkenyl or phenyl, thienyl, pyrrolyl or furyl (optionally εubεtituted with one to two εubstituentε independently εelected from (C M )alkyl, (C )alkyloxy, trifluoromethyl and halo) or - (CH^-R 12 in which x iε 0, 1, 2 or 3 and R 12 iε hydroxy, (C M )alkyloxy, -C(0)NR 13 R !4 , -NR 13 C(O)R 14 , -NR ,3 C(O)OR 14 , -SO j NR^R 14 , -NR ,3 S0 2 R 14 , -NR 13 S0 2 NR 1 R 13 or -NR 13 C(O)NR 14 R 13 in which R 13 , R 14 and R 13 are independently hydrogen, (C,.,)alkyl, trifluoromethyl or aryl; and R 7 is hydrogen, (C,^)alkyl or (C M )alkenyl or phenyl (C )alkyl (wherein the phenyl is optionally substituted with one to three subεtituentε independently selected from (C M )alkyloxy, methylenedioxy, ethylenedioxy or halo) or -(C__ 2 ) Z R 12 in which z is 2 or 3 and R 12 is aε defined above; and the pharmaceutically acceptable εaltε, individual iεomerε, and mixtures of isomerε thereof. 2. The compound of Claim 1 which haε the following formula (Formula I (a) ) : l(α) in which n is 3, 4 or 5; p is 0 or 1; R 1 is halo; R 3 is (C M )alkyloxy; and R 3 and R 6 are each (C )alkyl or together form -(CH^-, -(CH j ),;-, - (CHA) 2 0 S^) 2 - or -CHR 8 CH 2 CR 9 R 10 CHR 11 CH 2 - in which R 8 and R 11 are each hydrogen or together are -(CH-),- in which t iε 1, 2 or 3, R 9 is hydrogen, hydroxy, (C,_j)alkyl, (C M )alkenyl or (C M )alkyloxy, and R 10 is hydrogen, (C,^,)alkyl or (C M )alkenyl or phenyl, thienyl, pyrrolyl or furyl (optionally εubεtituted with one to two substituentε independently selected from (C,.,)alkyl, (C M )alkyloxy, trifluoromethyl and halo) or -(CR^.R 12 in which x is 0, 1, 2 or 3 and R 12 is hydroxy, (C )alkyloxy, -C(0)NR 13 R 14 , -NR 13 C(0)R 14 , -NR 13 C(O)OR 14 , -SOzNR^R 14 , -NR I3 S0 2 R 14 , -N 13 Sθ 2 N 1 13 or -NR I3 C(O)NR 14 R 13 in which R 13 , R 14 and R 1S are independently hydrogen, (C M )alkyl or trifluoromethyl; and the pharmaceutically acceptable salts, individual isomers, and mixtures of isomers thereof. 3. The compound of Claim 2 in which p is 0 and R 3 and R 6 together form -CHR 8 CH,,CCRR 99 RR l100 CCHHRR ππ CCHH,,- . 4. The compound of Claim 3 in which n is . 5. The compound of Claim 4 in which R 1 is chloro, R 3 is methoxy and each R 8 , R 9 and R" is hydrogen. 6. The compound of Claim 5 in which R 10 iε hydrogen, namely 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (piperidinyl-l-yl)pentan-l-one and the pharmaceutically acceptable salts thereof. 7. The compound of Claim 6 which iε 1- (4-amino-5-chloro- 2-methoxyphenyl) -5- (piperidinyl-l-yl)pentan-l-one hydrochloride. 8. The compound of Claim 5 in which R 10 iε methyl, namely 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (4-methylpiperidinyl-1-yl)pentan-1-one and the pharmaceutically acceptable εaltε thereof. 9. The compound of Claim 8 which iε 1- (4-amino-5-chloro- 2-methoxyphenyl) -5- (4-methylpiperidinyl-1-yl)pentan-l-one hydrochloride. 10. The compound of Claim 1 which haε the following formula (Formula I (b) ) : in which p is 0 or 1; q iε 1 or 2; R 1 is halo; R 2 is hydrogen or (C M )alkyloxy and R 3 is (C M )alkyloxy or R 2 and R 3 together are methylenedioxy or ethylenedioxy; and R 7 iε hydrogen, (C,^)alkyl, (C M )alkenyl or phenyl (C M )alkyl (wherein the phenyl iε optionally substituted with one to three substituents independently selected from (C )alkyloxy, methylenedioxy, ethylenedioxy or halo) or - (CH 2 )-R 12 in which z iε 2 or 3 and R 12 iε hydroxy, (C )alkyloxy, -C(0)NR 13 R 14 , -NR l3 C(0)R' 4 , -NR 13 C(0)OR 14 , -NR 13 S0 2 R 14 , -NR 13 S0 2 NR 1 R 13 or -NR l3 C(0)NR l R 13 in which R 13 , R 14 and R 13 are independently hydrogen, (C M )alkyl, trifluoromethyl or aryl; and the pharmaceutically acceptable salts, individual isomerε, and mixtureε of isomers thereof. 11. The compound of Claim 10 in which q is 2. 12. The compound of Claim 11 in which R 1 is chloro, R 2 iε hydrogen and R 3 iε methoxy. 13. The compound of Claim 12 in which p iε 0 and R 7 iε n-butyl, namely 1- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (n-butyl)piperdin-4- yl]propan-1-one and the pharmaceutically acceptable εaltε thereof. 14. The compound of Claim 13 which iε 1- (4-amino-5-chloro-2- methoxy-phenyl) -3- [1- (n-butyl)piperdin-4-yl]propan-l-one hydrochloride. 15. The compound of Claim 12 in which p iε 0 and R 7 iε 2- [ (methylεulfonyl)amino]ethyl, namely 1- (4-amino-5-chloro-2- methoxyphenyl) -3-{2- [(methylεulfonyl)amino]ethyl}piperdin-4-yl]propan-1-one and the pharmaceutically acceptable salts thereof. 16. The compound of Claim 15 which is 1- (4-amino-5-chloro- 2-methoxy-phenyl) -3-{2- [ (methylsulfonyl)amino]ethyl}piperdin-4-yl] ropan-1- one hydrochloride. 17. The compound of Claim 12 in which p is 0 and R 7 iε 3- (3,4-dimethoxyphenyl)prop-1-yl, namely 1- (4-amino-5-chloro-2- methoxyphenyl) -3-{l- [3- (3,4-dimethoxyphenyl)prop-l-yl]piperdin-4-yl}propan- l-one and the pharmaceutically acceptable salts thereof. 18. The compound of Claim 17 which is 1- (4-amino-5-chloro-2- methoxy-phenyl) -3-{l- [3- (3,4-dimethoxyphenyl)prop-l-yl]piperdin-4- yl}propan-l-one hydrochloride. 19. The compound of Claim 11 in which R 1 is chloro and R 2 and R 3 together are ethylenedioxy. 20. The compound of Claim 19 in which p is 0 and R 7 is 3- ( -methoxyphenyl)prop-1-yl, namely 1- (4-amino-5-chloro-2,3-ethylenedioxy¬ phenyl) -3-{l- [3- (4-methoxyphenyl)prop-l-yl]piperdin-4-yl}propan-l-one and the pharmaceutically acceptable salts thereof. 21. The compound of Claim 20 which is 3- (4-methoxyphenyl)prop-1-yl, namely 1- (4-amino-5-chloro-2,3-ethylenedioxyphenyl) - 3-{l- [3- (4-methoxyphenyl) -prop-l-yl]piperdin-4-yl}propan-l-one hydrochloride. 22. The compound of Claim 1 which has the following formula (Formula I (c) ) : in which R 1 iε halo; R 3 iε (C._,)alkylphenyloxy ( (wherein the phenyl iε optionally substituted with one to three substituentε independently selected from halo, hydroxy, (C M )alkyl, (C )alkyloxy, nitro, amino, aminocarbonyl, (C M )alkylamino, di (C M )alkylamino, (C )alkanoylamino and 3,4-methylenedioxy) ; and R 4 iε a group of Formula (a) or (b) : in which n iε 3, 4 or 5; p is 0 or 1; q iε 1 or 2; R 5 and R 6 are each (C M )alkyl or together form - HA) A - , - (CH j ) 2 0(CH 2 ) 2 - or -CHR 8 CH 2 CRR I0 CHR 11 CH 2 - in which R 8 and R" are each hydrogen or together are -(CHj),- in which t is 1, 2 or 3, R 9 iε hydrogen, hydroxy, (C,^)alkyl, (C M )alkenyl or (C )alkyloxy and R 10 is hydrogen, (C w )alkyl or (C M )alkenyl or phenyl, thienyl, pyrrolyl or furyl (optionally substituted with one to two substituents independently selected from (C]^)alkyl, (C )alkyloxy, trifluoromethyl and halo) or -(αy.R 12 in which x is 0, 1, 2 or 3 and R 12 is hydroxy, (C )alkyloxy, -C(0)NR 13 R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)OR 14 , -S0 2 NR 13 R 14 , -NR 13 S0 2 R 14 , -NR 13 SO_NR l4 R 13 or -NR 13 C(0)NR 14 R 13 in which R 13 , R 14 and R 13 are independently hydrogen, (C M )alkyl or trifluoromethyl; and R 7 is hydrogen, (C,^)alkyl or (C M )alkenyl or phenyl (C M )alkyl (wherein the phenyl is optionally substituted with one to three substituentε independently εelected from (C )alkyloxy, methylenedioxy, ethylenedioxy or halo) or -(CH j )-R 12 in which z iε 2 or 3 and R 12 is as defined above; and the pharmaceutically acceptable εalts, individual isomerε, and mixtureε of iεomerε thereof. 23. A compound of Claim 22 in which R 3 iε optionally εubεtituted phenyl (C M )alkyloxy and R 4 iε a group of Formula (a) . 24. A compound of Claim 23 in which R 3 and R 6 together form -CHR 8 CH: 2 ,CCRR 99 RR 1100 CCHHRR" 1 'CCHH 2 - . 25. A compound of Claim 24 in which n is 4. 26. A compound of Claim 22 in which R 3 is optionally substituted phenyl (C M )alkyloxy and R 4 iε a group of Formula (b) . 27. A compound of Claim 26 in which q iε 2. 28. A pharmaceutical compoεition compriεing a therapeutically effective amount of a compound of Claimε 1-27. 29. A method for treating a condition which can be ameliorated by a drug which interacts with 5-HT 4 receptors in an animal in need of such treatment, which method comprises administering to such an animal a therapeutically effective amount of a compound of Claims 1-27. 30. The method of Claim 29 in which the condition is chosen from a CNS disorder, a gastrointestinal disorder, a cardiovascular disorder, and a urinary tract disorder. 31. A process for the preparation of a compound of Formula I: in which R 1 is halo; R 2 is hydrogen or (C M )alkyloxy and R 3 is (C )alkyloxy or phenyl (C M )alkyloxy (wherein the phenyl iε optionally εubεtituted with one to three εubεtituentε independently εelected from halo, hydroxy, (C M )alkyl, (C )alkyloxy, nitro, amino, aminocarbonyl, (C M )alkylamino, di (C M )alkylamino, (C M )alkanoylamino and 3,4-methylenedioxy) or R 2 and R 3 together are methylenedioxy or ethylenedioxy; and R 4 iε a group of Formula (a) or (b) in which n is 3, 4 or 5; p is 0 or 1; q is 1 or 2; R 3 and R 6 are each (C M )alkyl or together form -(CH 2 ) 4 -, - (CH *_ 2 /)« ( - - (CH 2 ) 2 0(CH 2 ) 2 - or -CHR 8 CH 2 CR 9 R I0 CHR"CH 2 - in which R 8 and R 11 are each hydrogen or together are -(CH , ),- in which t is l, 2 or 3, R 9 iε hydrogen, hydroxy, (C,^)alkyl, (C M )alkenyl or (C )alkyloxy and R 10 is hydrogen, (C^)alkyl or (C M )alkenyl or phenyl, thienyl, pyrrolyl or furyl (optionally substituted with one to two subεtituents independently selected from (C M )alkyl, (C )alkyloxy, trifluoromethyl and halo) or -(CHj).R 12 in which x is 0, 1, 2 or 3 and R 12 is hydroxy, (C )alkyloxy, -C(0)NR 13 R 14 , -NR 13 C(0)R 14 , -NR 13 C(O)OR 14 , or -NR 13 C(0)NR 14 R 13 in which R 13 , R 14 and R 15 are independently hydrogen, (C,,,)alkyl, trifluoromethyl or aryl; and R 7 is hydrogen, (C,.g)alkyl or (C M )alkenyl or phenyl (C )alkyl (wherein the phenyl is optionally substituted with one to three substituents independently selected from (C M )alkyloxy, methylenedioxy, ethylenedioxy or halo) or -(Ciy.R 12 in which z is 2 or 3 and R 12 is as defined above; and the pharmaceutically acceptable salts, individual isomers, and mixtures of isomerε thereof, which proceεs comprises: (A) reacting, in the presence of a strong base, a compound of Formula II: I I or the protected derivative thereof, in which R 4 is as defined in the preamble of thiε claim; with a compound of Formula III: in which each R 1 , R 2 and R 3 are aε defined in the preamble of thiε claim; acidifying; decarboxylating; and when neceεεary removing any protective groups; or (B) for the preparation of a compound of Formula I in which R 2 is hydrogen and R 4 iε a group of Formula (a) , reacting, in the preεence of a Lewiε acid, a compound of Formula V: in which P is a protective group and R 1 is halo, with a compound of Formula VI: in which R 18 is halo or hydroxy and R 19 is halo and n iε 3, 4 or 5; alkylating with a compound of the formula L-R 3 in which L is a leaving group and R 3 is as defined above; reacting with a compound the formula HNR 5 R 6 , or the _>7-oxide thereof, in which R 3 and R 6 are as defined above; and deprotecting; or (C) for the preparation of a compound of Formula I in which R 4 is a group of Formula (b) wherein p is 0 and q is 2, reacting a compound of Formula VTII: in which R 1 , R 2 and R 3 are as defined in the preamble of this claim; with a compound of Formula IX: in which R 7 iε aε defined in the preamble of thiε claim; dehydrating; and then hydrogenating; or IX (D) for the preparation of a compound of Formula I in which R 4 iε a group of Formula (a) , treating a compound of Formula XI: Br„ ,C I ( CH 2)- XI in which n is as defined in the preamble of thiε claim, with magneεium to give a corresponding Grignard reagent, reacting the Grignard reagent with a compound of Formula XII: in which each P is a protective group and R 1 , R 2 and R 3 are aε defined in the preamble of this claim, deprotecting and then reacting with a compound of the formula NHR 5 R 6 ; or (E) for the preparation of a compound of Formula I in which R 4 is a group of Formula (a) , reacting, in the preεence of a εtrong base, a compound of Formula II (a) : ll(_) in which R 3 and R* is aε defined in the preamble of thiε claim, with a compound of Formula XIII: X I I I in which each P iε a protective group and R 1 , R 2 and R 3 are aε defined in the preamble of this claim; or (F) optionally alkylating a compound of Formula I in which R 4 is a group of Formula (b) and R 7 iε hydrogen with a compound of the formula L-R 20 in which L is leaving group and R 20 is (C )alkyl, (C M )alkenyl, phenyl (C M )alkyl (wherein the phenyl is optionally substituted with one to three substituents independently selected from (C )alkyloxy, methylenedioxy, ethylenedioxy or halo) or L- (CH 2 )_R 12 (wherein z and R 12 are as defined in the preamble of thiε claim) to give a compound of Formula I in which R 4 is a group of Formula (b) wherein R 7 is not hydrogen; or (G) optionally alkylating a compound of Formula I in which R 4 is a group of Formula (b) and R 7 is hydrogen with a compound of the formula X-R 21 in which X is azacycloprop-1-yl and R 21 is -C(0)R 14 , -S0 2 R 14 , -SOaNR^R 13 or - CONR 14 R ls (wherein R 14 and R 13 are as defined in the preamble of this claim) to give a compound of Formula I in which R 4 is a group of Formula (b) wherein R 7 is -CH 2 CH 2 ___C(0)R 14 , -CH 2 CH 2 ___S0 2 R !4 , -CH 2 CH 2 NHSθ 2 NR l4 R 13 or -CH 2 CH 2 NHCONR 14 R 13 ; or (H) optionally demethylating a compound of Formula I in which R 3 is methoxy, and then alkylating with a compound of the formula L-R 22 in which R 22 is (C^)alkyl or phenyl (C M )alkyl (wherein the phenyl iε optionally substituted with one to three substituents independently selected from halo, hydroxy, (C M )alkyl, (C M )alkyloxy, nitro, amino, aminocarbonyl, (C M )alkylamino, di (C M )alkylamino, (C )alkanoylamino and 3,4-methylenedioxy) to give a compound of Formula I in which R 3 is (C M )alkyloxy or phenyl (C M )alkyloxy (wherein the phenyl is optionally subεtituted as defined in the preamble of this claim) ; or (I) optionally oxidizing a compound of Formula I in which p iε 0 to give a compound of Formula I in which p is 1; or (J) optionally reducing a compound of Formula I in which p iε 1 to give a compound of Formula I in which p is 0; or (K) optionally reacting the corresponding non-εalt form of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid or base to give a pharmaceutically acceptable salt; or (L) optionally reacting the correεponding acid addition εalt or baεe addition εalt form of a compound of Formula I with a suitable baεe or acid, reεpectively, to give the free acid or free base.

Inventors: CLARK ROBIN D, EGLEN RICHARD, GARDNER JOHN O, JAHANGIR ALAM, MILLER AARON B, CLARK, ROBIN, D., EGLEN, RICHARD, GARDNER, JOHN, O., JAHANGIR, ALAM, MILLER, AARON, B.
Applicants: SYNTEX INC, SYNTEX (U.S.A.) INC.
Application year: 1994
Main classification: C07D211
IPC codes: A61K31, A61P1, A61P9, A61P13, A61P15, A61P25, A61P43, C07C225, C07C239, C07C259, C07D207, C07D211, C07D213, C07D295, C07D317, C07D319, C07D405, C07D487